Skip to main content

Advertisement

SpringerLink
Log in

The Immune System in Stroke: Clinical Challenges and Their Translation to Experimental Research

  • INVITED REVIEW
  • Published:
Journal of Neuroimmune Pharmacology Aims and scope Submit manuscript

Abstract

Stroke represents an unresolved challenge for both developed and developing countries and has a huge socio-economic impact. Although considerable effort has been made to limit stroke incidence and improve outcome, strategies aimed at protecting injured neurons in the brain have all failed. This failure is likely to be due to both the incompleteness of modelling the disease and its causes in experimental research, and also the lack of understanding of how systemic mechanisms lead to an acute cerebrovascular event or contribute to outcome. Inflammation has been implicated in all forms of brain injury and it is now clear that immune mechanisms profoundly influence (and are responsible for the development of) risk and causation of stroke, and the outcome following the onset of cerebral ischemia. Until very recently, systemic inflammatory mechanisms, with respect to common comorbidities in stroke, have largely been ignored in experimental studies. The main aim is therefore to understand interactions between the immune system and brain injury in order to develop novel therapeutic approaches. Recent data from clinical and experimental research clearly show that systemic inflammatory diseases –such as atherosclerosis, obesity, diabetes or infection – similar to stress and advanced age, are associated with dysregulated immune responses which can profoundly contribute to cerebrovascular inflammation and injury in the central nervous system. In this review, we summarize recent advances in the field of inflammation and stroke, focusing on the challenges of translation between pre-clinical and clinical studies, and potential anti-inflammatory/immunomodulatory therapeutic approaches.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  • Afonso PV, Ozden S, Prevost MC, Schmitt C, Seilhean D, Weksler B, Couraud PO, Gessain A, Romero IA, Ceccaldi PE (2007) Human blood–brain barrier disruption by retroviral-infected lymphocytes: role of myosin light chain kinase in endothelial tight-junction disorganization. J Immunol 179(4):2576–2583

    PubMed  CAS  Google Scholar 

  • Akopov SE, Simonian NA, Grigorian GS (1996) Dynamics of polymorphonuclear leukocyte accumulation in acute cerebral infarction and their correlation with brain tissue damage. Stroke j cereb circ 27(10):1739–1743

    Article  CAS  Google Scholar 

  • Allan SM, Tyrrell PJ, Rothwell NJ (2005) Interleukin-1 and neuronal injury. Nat Rev Immunol 5(8):629–640

    Article  PubMed  CAS  Google Scholar 

  • Andaluz-Ojeda D, Iglesias V, Bobillo F, Almansa R, Rico L, Gandia F, Loma AM, Nieto C, Diego R, Ramos E, Nocito M, Resino S, Eiros J, Tamayo E, de Lejarazu R, Bermejo-Martin J (2011) Early natural killer cell counts in blood predict mortality in severe sepsis. Crit Care 15(5):R243

    Article  PubMed  Google Scholar 

  • Andersen KK, Andersen ZJ, Olsen TS (2011) Predictors of early and late case-fatality in a nationwide Danish study of 26,818 patients with first-ever ischemic stroke. Stroke j cereb circ 42(10):2806–2812. doi:10.1161/STROKEAHA.111.619049

    Article  Google Scholar 

  • Appelros P, Stegmayr B, Terent A (2009) Sex differences in stroke epidemiology: a systematic review. Stroke j cereb circ 40(4):1082–1090. doi:10.1161/STROKEAHA.108.540781

    Article  Google Scholar 

  • Asahi M, Asahi K, Jung JC, del Zoppo GJ, Fini ME, Lo EH (2000) Role for matrix metalloproteinase 9 after focal cerebral ischemia: effects of gene knockout and enzyme inhibition with BB-94. J Cereb Blood Flow Metab 20(12):1681–1689

    Article  PubMed  CAS  Google Scholar 

  • Aslanyan S, Weir CJ, Diener HC, Kaste M, Lees KR (2004) Pneumonia and urinary tract infection after acute ischaemic stroke: a tertiary analysis of the GAIN International trial. Eur j neurol: off j Eur Fed Neurol Soc 11(1):49–53

    CAS  Google Scholar 

  • Balkaya M, Prinz V, Custodis F, Gertz K, Kronenberg G, Kroeber J, Fink K, Plehm R, Gass P, Laufs U, Endres M (2011) Stress worsens endothelial function and ischemic stroke via glucocorticoids. Stroke j cereb circ 42(11):3258–3264. doi:10.1161/strokeaha.110.607705

    Article  CAS  Google Scholar 

  • Banasr M, Duman RS (2007) Regulation of neurogenesis and gliogenesis by stress and antidepressant treatment. CNS Neurol Disord Drug Targets 6(5):311–320

    Article  PubMed  CAS  Google Scholar 

  • Barath P, Fishbein MC, Cao J, Berenson J, Helfant RH, Forrester JS (1990) Detection and localization of tumor necrosis factor in human atheroma. Am J Cardiol 65(5):297–302

    Article  PubMed  CAS  Google Scholar 

  • Baybutt HN, Holsboer F (1990) Inhibition of macrophage differentiation and function by cortisol. Endocrinology 127(1):476–480. doi:10.1210/endo-127-1-476

    Article  PubMed  CAS  Google Scholar 

  • Bisoendial RJ, Birjmohun RS, Akdim F, van ’t Veer C, Spek CA, Hartman D, de Groot ER, Bankaitis-Davis DM, Kastelein JJ, Stroes ES (2009) C-reactive protein elicits white blood cell activation in humans. Am J Med 122(6):582 e581–589. doi:10.1016/j.amjmed.2008.11.032

    Article  CAS  Google Scholar 

  • Bisoendial RJ, Kastelein JJ, Levels JH, Zwaginga JJ, van den Bogaard B, Reitsma PH, Meijers JC, Hartman D, Levi M, Stroes ES (2005) Activation of inflammation and coagulation after infusion of C-reactive protein in humans. Circ Res 96(7):714–716. doi:10.1161/01.RES.0000163015.67711.AB

    Article  PubMed  CAS  Google Scholar 

  • Bomont L, MacKenzie ET (1995) Neuroprotection after focal cerebral ischaemia in hyperglycaemic and diabetic rats. Neurosci Lett 197(1):53–56

    Article  PubMed  CAS  Google Scholar 

  • Bousser M-G (2012) Stroke prevention: an update. Front Med 6(1):22–34

    Article  PubMed  Google Scholar 

  • Bradshaw EM, Raddassi K, Elyaman W, Orban T, Gottlieb PA, Kent SC, Hafler DA (2009) Monocytes from patients with type 1 diabetes spontaneously secrete proinflammatory cytokines inducing Th17 cells. J Immunol 183(7):4432–4439. doi:10.4049/jimmunol.0900576

    Article  PubMed  CAS  Google Scholar 

  • Brandes RP, Fleming I, Busse R (2005) Endothelial aging. Cardiovasc Res 66(2):286–294. doi:10.1016/j.cardiores.2004.12.027

    Article  PubMed  CAS  Google Scholar 

  • Brown RD, Whisnant JP, Sicks JD, O’Fallon WM, Wiebers DO (1996) Stroke incidence, prevalence, and survival: secular trends in Rochester, Minnesota, through 1989. Stroke j cereb circ 27(3):373–380

    CAS  Google Scholar 

  • Calderon B, Suri A, Unanue ER (2006) In CD4+ T-cell-induced diabetes, macrophages are the final effector cells that mediate islet Î2-cell killing: studies from an acute model. Am J Pathol 169(6):2137–2147

    Article  PubMed  CAS  Google Scholar 

  • Caso JR, Hurtado O, Pereira MP, Garcia-Bueno B, Menchen L, Alou L, Gomez-Lus ML, Moro MA, Lizasoain I, Leza JC (2009) Colonic bacterial translocation as a possible factor in stress-worsening experimental stroke outcome. Am J Physiol Regul Integr Comp Physiol 296(4):R979–R985

    Article  PubMed  CAS  Google Scholar 

  • Caso JR, Lizasoain I, Lorenzo P, Moro MA, Leza JC (2006) The role of tumor necrosis factor-alpha in stress-induced worsening of cerebral ischemia in rats. Neuroscience 142(1):59–69. doi:10.1016/j.neuroscience.2006.06.009

    Article  PubMed  CAS  Google Scholar 

  • Celi A, Cianchetti S, Dell’Omo G, Pedrinelli R (2010) Angiotensin II, tissue factor and the thrombotic paradox of hypertension. Expert Rev Cardiovasc Ther 8(12):1723–1729

    Article  PubMed  CAS  Google Scholar 

  • Chae CU, Lee RT, Rifai N, Ridker PM (2001) Blood pressure and inflammation in apparently healthy men. Hypertension 38(3):399–403. doi:10.1161/01.hyp.38.3.399

    Article  PubMed  CAS  Google Scholar 

  • Chamorro A, Meisel A, Planas AM, Urra X, van de Beek D, Veltkamp R (2012) The immunology of acute stroke. Nat rev Neurol 8(7):401–410. doi:10.1038/nrneurol.2012.98

    Article  PubMed  CAS  Google Scholar 

  • Chen J, Cui X, Zacharek A, Cui Y, Roberts C, Chopp M (2011) White matter damage and the effect of matrix metalloproteinases in type 2 diabetic mice after stroke. Stroke j cereb circ 42(2):445–452

    Article  CAS  Google Scholar 

  • Chen Z, Yang G, Offer A, Zhou M, Smith M, Peto R, Ge H, Yang L, Whitlock G (2012) Body mass index and mortality in China: a 15-year prospective study of 220 000 men. Int J Epidemiol 41(2):472–481

    Article  PubMed  Google Scholar 

  • Chen ZM, Sandercock P, Pan HC, Counsell C, Collins R, Liu LS, Xie JX, Warlow C, Peto R (2000) Indications for early aspirin use in acute ischemic stroke : a combined analysis of 40 000 randomized patients from the chinese acute stroke trial and the international stroke trial. On behalf of the CAST and IST collaborative groups. Stroke j cereb circ 31(6):1240–1249

    Article  CAS  Google Scholar 

  • Clayton TC, Thompson M, Meade TW (2008) Recent respiratory infection and risk of cardiovascular disease: case–control study through a general practice database. Eur Hear J 29(1):96–103. doi:10.1093/eurheartj/ehm516

    Article  Google Scholar 

  • Coe CL, Rosenberg LT, Levine S (1988) Effect of maternal separation on the complement system and antibody responses in infant primates. Int J Neurosci 40(3–4):289–302. doi:10.3109/00207458808990717

    Article  PubMed  CAS  Google Scholar 

  • Cole DJ, Patel PM, Reynolds L, Drummond JC, Marcantonio S (1993) Temporary focal cerebral ischemia in spontaneously hypertensive rats: the effect of ibuprofen on infarct volume. J Pharmacol Exp Ther 266(3):1713–1717

    PubMed  CAS  Google Scholar 

  • Correa F, Gauberti M, Parcq J, Macrez R, Hommet Y, Obiang P, Hernangomez M, Montagne A, Liot G, Guaza C, Maubert E, Ali C, Vivien D, Docagne F (2011) Tissue plasminogen activator prevents white matter damage following stroke. J exp med 208(6):1229–1242. doi:10.1084/jem.20101880

    Article  PubMed  CAS  Google Scholar 

  • Dalekos GN, Elisaf M, Bairaktari E, Tsolas O, Siamopoulos KC (1997) Increased serum levels of interleukin-1β in the systemic circulation of patients with essential hypertension: additional risk factor for atherogenesis in hypertensive patients? J Lab Clin Med 129(3):300–308

    Article  PubMed  CAS  Google Scholar 

  • Dali-Youcef N, Mecili M, Ricci R, Andres E (2012) Metabolic inflammation: Connecting obesity and insulin resistance. Ann med

  • Dawson DA, Martin D, Hallenbeck JM (1996) Inhibition of tumor necrosis factor-alpha reduces focal cerebral ischemic injury in the spontaneously hypertensive rat. Neurosci Lett 218(1):41–44

    Article  PubMed  CAS  Google Scholar 

  • del Zoppo GJ, Milner R (2006) Integrin-matrix interactions in the cerebral microvasculature. Arterioscler Thromb Vasc Biol 26(9):1966–1975

    Article  PubMed  CAS  Google Scholar 

  • Denes A, Drake C, Stordy J, Chamberlain J, McColl BW, Gram H, Crossman D, Francis S, Allan SM, Rothwell NJ (2012) Interleukin-1 mediates neuroinflammatory changes associated with diet-induced atherosclerosis. J Am Heart Assoc 1(3):e002006. doi:10.1161/JAHA.112.002006

    Article  PubMed  CAS  Google Scholar 

  • Denes A, Ferenczi S, Halasz J, Kornyei Z, Kovacs KJ (2008) Role of CX3CR1 (fractalkine receptor) in brain damage and inflammation induced by focal cerebral ischemia in mouse. J cereb blood flow metab: off j Int Soc Cereb Blood Flow Metab 28(10):1707–1721

    Article  CAS  Google Scholar 

  • Denes A, Ferenczi S, Kovacs KJ (2011a) Systemic inflammatory challenges compromise survival after experimental stroke via augmenting brain inflammation, blood- brain barrier damage and brain oedema independently of infarct size. J neuroinflammation 8:164. doi:10.1186/1742-2094-8-164

    Article  PubMed  CAS  Google Scholar 

  • Denes A, Humphreys N, Lane TE, Grencis R, Rothwell N (2010a) Chronic systemic infection exacerbates ischemic brain damage via a CCL5 (regulated on activation, normal T-cell expressed and secreted)-mediated proinflammatory response in mice. J neurosci: off j Soc Neurosci 30(30):10086–10095. doi:10.1523/JNEUROSCI.1227-10.2010

    Article  CAS  Google Scholar 

  • Denes A, Pinteaux E, Rothwell NJ, Allan SM (2011b) Interleukin-1 and stroke: biomarker, harbinger of damage, and therapeutic target. Cerebrovasc Dis 32(6):517–527. doi:10.1159/000332205

    Article  PubMed  CAS  Google Scholar 

  • Denes A, Thornton P, Rothwell NJ, Allan SM (2010b) Inflammation and brain injury: acute cerebral ischaemia, peripheral and central inflammation. Brain behav immun 24(5):708–723. doi:10.1016/j.bbi.2009.09.010

    Article  PubMed  CAS  Google Scholar 

  • Derosa G, Ferrari I, D’Angelo A, Tinelli C, Salvadeo SA, Ciccarelli L, Piccinni MN, Gravina A, Ramondetti F, Maffioli P, Cicero AF (2008) Matrix metalloproteinase-2 and −9 levels in obese patients. Endothelium 15(4):219–224

    Article  PubMed  CAS  Google Scholar 

  • DeVries AC, Joh HD, Bernard O, Hattori K, Hurn PD, Traystman RJ, Alkayed NJ (2001) Social stress exacerbates stroke outcome by suppressing Bcl-2 expression. Proc Natl Acad Sci U S A 98(20):11824–11828. doi:10.1073/pnas.201215298

    Article  PubMed  CAS  Google Scholar 

  • Di Carlo A, Lamassa M, Baldereschi M, Pracucci G, Basile AM, Wolfe CD, Giroud M, Rudd A, Ghetti A, Inzitari D (2003) Sex differences in the clinical presentation, resource use, and 3-month outcome of acute stroke in Europe: data from a multicenter multinational hospital-based registry. Stroke j cereb circ 34(5):1114–1119. doi:10.1161/01.STR.0000068410.07397.D7

    Article  Google Scholar 

  • Di Napoli M, Papa F, Bocola V (2001) C-reactive protein in ischemic stroke: an independent prognostic factor. Stroke j cereb circ 32(4):917–924

    Article  Google Scholar 

  • Di Napoli M, Schwaninger M, Cappelli R, Ceccarelli E, Di Gianfilippo G, Donati C, Emsley HC, Forconi S, Hopkins SJ, Masotti L, Muir KW, Paciucci A, Papa F, Roncacci S, Sander D, Sander K, Smith CJ, Stefanini A, Weber D (2005) Evaluation of C-reactive protein measurement for assessing the risk and prognosis in ischemic stroke: a statement for health care professionals from the CRP Pooling Project members. Stroke j cereb circ 36(6):1316–1329. doi:10.1161/01.STR.0000165929.78756.ed

    Article  CAS  Google Scholar 

  • Dinapoli VA, Benkovic SA, Li X, Kelly KA, Miller DB, Rosen CL, Huber JD, O’Callaghan JP (2010) Age exaggerates proinflammatory cytokine signaling and truncates signal transducers and activators of transcription 3 signaling following ischemic stroke in the rat. Neuroscience 170(2):633–644. doi:10.1016/j.neuroscience.2010.07.011

    Article  PubMed  CAS  Google Scholar 

  • DiNapoli VA, Huber JD, Houser K, Li X, Rosen CL (2008) Early disruptions of the blood–brain barrier may contribute to exacerbated neuronal damage and prolonged functional recovery following stroke in aged rats. Neurobiol aging 29(5):753–764. doi:10.1016/j.neurobiolaging.2006.12.007

    Article  PubMed  CAS  Google Scholar 

  • Dinarello CA (2011) Interleukin-1 in the pathogenesis and treatment of inflammatory diseases. Blood 117(14):3720–3732. doi:10.1182/blood-2010-07-273417

    Article  PubMed  CAS  Google Scholar 

  • Dinkel K, MacPherson A, Sapolsky RM (2003) Novel glucocorticoid effects on acute inflammation in the CNS. J Neurochem 84(4):705–716

    Article  PubMed  CAS  Google Scholar 

  • Dirnagl U, Klehmet J, Braun JS, Harms H, Meisel C, Ziemssen T, Prass K, Meisel A (2007) Stroke-induced immunodepression: experimental evidence and clinical relevance. Stroke j cereb circ 38(2 Suppl):770–773. doi:10.1161/01.STR.0000251441.89665.bc

    Article  Google Scholar 

  • Dong ZM, Wagner DD (1998) Leukocyte-endothelium adhesion molecules in atherosclerosis. J Lab Clin Med 132(5):369–375

    Article  PubMed  CAS  Google Scholar 

  • Drake C, Boutin H, Jones MS, Denes A, McColl BW, Selvarajah JR, Hulme S, Georgiou RF, Hinz R, Gerhard A, Vail A, Prenant C, Julyan P, Maroy R, Brown G, Smigova A, Herholz K, Kassiou M, Crossman D, Francis S, Proctor SD, Russell JC, Hopkins SJ, Tyrrell PJ, Rothwell NJ, Allan SM (2011) Brain inflammation is induced by co-morbidities and risk factors for stroke. Brain behav immun 25(6):1113–1122

    Article  PubMed  CAS  Google Scholar 

  • Du Q, Min S, Chen L-Y, Ma Y-D, Guo X-L, Wang Z, Wang Z-G (2012) Major stress hormones suppress the response of macrophages through down-regulation of TLR2 and TLR4. J Surg Res 173(2):354–361

    Article  PubMed  CAS  Google Scholar 

  • Dubal DB, Wise PM (2001) Neuroprotective effects of estradiol in middle-aged female rats. Endocrinology 142(1):43–48

    Article  PubMed  CAS  Google Scholar 

  • Duffaut C, Zakaroff-Girard A, Bourlier V, Decaunes P, Maumus M, Chiotasso P, Sengenes C, Lafontan M, Galitzky J, Bouloumie A (2009) Interplay between human adipocytes and T lymphocytes in obesity. Arterioscler Thromb Vasc Biol 29(10):1608–1614. doi:10.1161/atvbaha.109.192583

    Article  PubMed  CAS  Google Scholar 

  • Dziewas R, Ritter M, Usta N, Boentert M, Hor H, Dittrich R, Schäbitz WR, Ringelstein EB, Young P (2007) Atherosclerosis and obstructive sleep apnea in patients with ischemic stroke. Cerebrovasc Dis 24(1):122–126

    Article  PubMed  Google Scholar 

  • Egido JA, Castillo O, Roig B, Sanz I, Herrero MR, Garay MT, Garcia AM, Fuentes M, Fernandez C (2012) Is psycho-physical stress a risk factor for stroke? A case–control study. J Neurol Neurosurg Psychiatry 83(11):1104–1111. doi:10.1136/jnnp-2012-302420

    Article  PubMed  Google Scholar 

  • ElAli A, Doeppner TR, Zechariah A, Hermann DM (2011) Increased blood–brain barrier permeability and brain edema after focal cerebral ischemia induced by hyperlipidemia: role of lipid peroxidation and calpain-1/2, matrix metalloproteinase-2/9, and RhoA overactivation. Stroke j cereb circ 42(11):3238–3244. doi:10.1161/STROKEAHA.111.615559

    Article  CAS  Google Scholar 

  • Elewa HF, Kozak A, Johnson MH, Ergul A, Fagan SC (2007) Blood pressure lowering after experimental cerebral ischemia provides neurovascular protection. J Hypertens 25(4):855–859. doi:10.1097/HJH.0b013e3280149708

    Article  PubMed  CAS  Google Scholar 

  • Elkind MS, Carty CL, O’Meara ES, Lumley T, Lefkowitz D, Kronmal RA, Longstreth WT Jr (2011) Hospitalization for infection and risk of acute ischemic stroke: the Cardiovascular Health Study. Stroke j cereb circ 42(7):1851–1856. doi:10.1161/STROKEAHA.110.608588

    Article  Google Scholar 

  • Elkind MS, Luna JM, Moon YP, Boden-Albala B, Liu KM, Spitalnik S, Rundek T, Sacco RL, Paik MC (2010a) Infectious burden and carotid plaque thickness: the northern Manhattan study. Stroke j cereb circ 41(3):e117–e122. doi:10.1161/STROKEAHA.109.571299

    Article  Google Scholar 

  • Elkind MS, Ramakrishnan P, Moon YP, Boden-Albala B, Liu KM, Spitalnik SL, Rundek T, Sacco RL, Paik MC (2010b) Infectious burden and risk of stroke: the northern Manhattan study. Arch Neurol 67(1):33–38. doi:10.1001/archneurol.2009.271

    Article  PubMed  Google Scholar 

  • Emsley HC, Hopkins SJ (2008a) Acute ischaemic stroke and infection: recent and emerging concepts. Lancet Neurol 7(4):341–353. doi:10.1016/S1474-4422(08)70061-9

    Article  PubMed  Google Scholar 

  • Emsley HC, Smith CJ, Gavin CM, Georgiou RF, Vail A, Barberan EM, Hallenbeck JM, del Zoppo GJ, Rothwell NJ, Tyrrell PJ, Hopkins SJ (2003) An early and sustained peripheral inflammatory response in acute ischaemic stroke: relationships with infection and atherosclerosis. J Neuroimmunol 139(1–2):93–101

    Article  PubMed  CAS  Google Scholar 

  • Emsley HC, Smith CJ, Gavin CM, Georgiou RF, Vail A, Barberan EM, Illingworth K, Scarth S, Wickramasinghe V, Hoadley ME, Rothwell NJ, Tyrrell PJ, Hopkins SJ (2007) Clinical outcome following acute ischaemic stroke relates to both activation and autoregulatory inhibition of cytokine production. BMC Neurol 7:5. doi:10.1186/1471-2377-7-5

    Article  PubMed  CAS  Google Scholar 

  • Emsley HC, Smith CJ, Georgiou RF, Vail A, Hopkins SJ, Rothwell NJ, Tyrrell PJ (2005a) A randomised phase II study of interleukin-1 receptor antagonist in acute stroke patients. J Neurol Neurosurg Psychiatry 76(10):1366–1372. doi:10.1136/jnnp.2004.054882

    Article  PubMed  CAS  Google Scholar 

  • Emsley HC, Smith CJ, Georgiou RF, Vail A, Tyrrell PJ, Barberan EM, Rothwell NJ, Hopkins SJ (2005b) Correlation of systemic inflammatory response with infarct volume in acute ischemic stroke patients. Stroke j cereb circ 36(2):228–229. doi:10.1161/01.STR.0000155197.88944.ac, author reply 228–229

    Article  Google Scholar 

  • Emsley HC, Smith CJ, Tyrrell PJ, Hopkins SJ (2008) Inflammation in acute ischemic stroke and its relevance to stroke critical care. Neurocrit care 9(1):125–138. doi:10.1007/s12028-007-9035-x

    Article  PubMed  CAS  Google Scholar 

  • Emsley HCA, Hopkins SJ (2008b) Acute ischaemic stroke and infection: recent and emerging concepts. Lancet Neurol 7(4):341–353

    Article  PubMed  Google Scholar 

  • Enlimomab Acute Stroke Trial Investigators (2001) Use of anti-ICAM-1 therapy in ischemic stroke: results of the enlimomab acute stroke trial. Neurology 57:1428–1434

    Article  Google Scholar 

  • Ericsson A, Kovacs KJ, Sawchenko PE (1994) A functional anatomical analysis of central pathways subserving the effects of interleukin-1 on stress-related neuroendocrine neurons. J neurosci: off j Soc Neurosci 14(2):897–913

    CAS  Google Scholar 

  • Ershler WB, Keller ET (2000) Age-associated increased interleukin-6 gene expression, late-life diseases, and frailty. Ann Rev Med 51(1):245–270. doi:10.1146/annurev.med.51.1.245

    Article  PubMed  CAS  Google Scholar 

  • European cardiovascular disease statistics (2008) European cardiovascular disease statistics 2008. European Heart Network, Brussels

    Google Scholar 

  • Fassbender K, Dempfle CE, Mielke O, Rossol S, Schneider S, Dollman M, Hennerici M (1997) Proinflammatory cytokines: indicators of infection in high-risk patients. J lab clin med 130(5):535–539

    Article  PubMed  CAS  Google Scholar 

  • Fassbender K, Schmidt R, Mossner R, Daffertshofer M, Hennerici M (1994) Pattern of activation of the hypothalamic-pituitary-adrenal axis in acute stroke. Relation to acute confusional state, extent of brain damage, and clinical outcome. Stroke j cereb circ 25(6):1105–1108

    Article  CAS  Google Scholar 

  • Fieren MWJA (2012) The local inflammatory responses to infection of the peritoneal cavity in humans: their regulation by cytokines, macrophages, and other leukocytes. Mediat Inflamm 2012:9. doi:10.1155/2012/976241

    Article  CAS  Google Scholar 

  • Fisher M, Feuerstein G, Howells DW, Hurn PD, Kent TA, Savitz SI, Lo EH (2009) Update of the stroke therapy academic industry roundtable preclinical recommendations. Stroke j cereb circ 40(6):2244–2250

    Article  Google Scholar 

  • Fleshner M (2012) Stress-evoked sterile inflammation, danger associated molecular patterns (DAMPs), microbial associated molecular patterns (MAMPs) and the inflammasome. Brain behav immun. doi:10.1016/j.bbi.2012.08.012

    Google Scholar 

  • Fleshner M, Campisi J, Deak T, Greenwood BN, Kintzel JA, Leem TH, Smith TP, Sorensen B (2002) Acute stressor exposure facilitates innate immunity more in physically active than in sedentary rats. Am J Physiol Regul Integr Comp Physiol 282(6):R1680–R1686. doi:10.1152/ajpregu.00661.2001

    PubMed  CAS  Google Scholar 

  • Fleshner M, Nguyen KT, Cotter CS, Watkins LR, Maier SF (1998) Acute stressor exposure both suppresses acquired immunity and potentiates innate immunity. Regul Integr Physiol 275(3):R870–R878

    CAS  Google Scholar 

  • Frank MG, Thompson BM, Watkins LR, Maier SF (2012) Glucocorticoids mediate stress-induced priming of microglial pro-inflammatory responses. Brain behav immun 26(2):337–345

    Article  PubMed  CAS  Google Scholar 

  • Friedrichs K, Klinke A, Baldus S (2011) Inflammatory pathways underlying atrial fibrillation. Trends mol med 17(10):556–563. doi:10.1016/j.molmed.2011.05.007

    Article  PubMed  CAS  Google Scholar 

  • Galea J, Armstrong J, Gadsdon P, Holden H, Francis SE, Holt CM (1996) Interleukin-1β in coronary arteries of patients with ischemic heart disease. Arterioscler Thromb Vasc Biol 16(8):1000–1006. doi:10.1161/01.atv.16.8.1000

    Article  PubMed  CAS  Google Scholar 

  • Garate I, Garcia-Bueno B, Madrigal JL, Caso JR, Alou L, Gomez-Lus ML, Mico JA, Leza JC (2012) Stress-induced neuroinflammation: role of the toll-like receptor-4 pathway. Biol Psychiatry. doi:10.1016/j.biopsych.2012.07.005

    PubMed  Google Scholar 

  • Garcia JH, Liu KF, Relton JK (1995) Interleukin-1 receptor antagonist decreases the number of necrotic neurons in rats with middle cerebral artery occlusion. Am J Pathol 147(5):1477–1486

    PubMed  CAS  Google Scholar 

  • Gerhard A, Neumaier B, Elitok E, Glatting G, Ries V, Tomczak R, Ludolph AC, Reske SN (2000) In vivo imaging of activated microglia using [11C]PK11195 and positron emission tomography in patients after ischemic stroke. Neuroreport 11(13):2957–2960

    Article  PubMed  CAS  Google Scholar 

  • Ghanim H, Aljada A, Hofmeyer D, Syed T, Mohanty P, Dandona P (2004) Circulating mononuclear cells in the obese are in a proinflammatory state. Circulation 110(12):1564–1571

    Article  PubMed  CAS  Google Scholar 

  • Gidday JM, Gasche YG, Copin JC, Shah AR, Perez RS, Shapiro SD, Chan PH, Park TS (2005) Leukocyte-derived matrix metalloproteinase-9 mediates blood–brain barrier breakdown and is proinflammatory after transient focal cerebral ischemia. Am J Physiol Heart Circ Physiol 289(2):H558–H568

    Article  PubMed  CAS  Google Scholar 

  • Glowinska-Olszewska B, Urban M (2007) Elevated matrix metalloproteinase 9 and tissue inhibitor of metalloproteinase 1 in obese children and adolescents. Metabolism 56(6):799–805

    Article  PubMed  CAS  Google Scholar 

  • Gomez CR, Hirano S, Cutro BT, Birjandi S, Baila H, Nomellini V, Kovacs EJ (2007) Advanced age exacerbates the pulmonary inflammatory response after lipopolysaccharide exposure. Crit Care Med 35(1):246–251

    Article  PubMed  CAS  Google Scholar 

  • Graebe M, Pedersen SF, Borgwardt L, Hojgaard L, Sillesen H, Kjaer A (2009) Molecular pathology in vulnerable carotid plaques: correlation with [18]-fluorodeoxyglucose positron emission tomography (FDG-PET). Eur j vasc endovasc surg: off j Eur Soc Vasc Surg 37(6):714–721. doi:10.1016/j.ejvs.2008.11.018

    Article  CAS  Google Scholar 

  • Grau AJ, Buggle F, Heindl S, Steichen-Wiehn C, Banerjee T, Maiwald M, Rohlfs M, Suhr H, Fiehn W, Becher H et al (1995) Recent infection as a risk factor for cerebrovascular ischemia. Stroke j cereb circ 26(3):373–379

    Article  CAS  Google Scholar 

  • Grau AJ, Urbanek C, Palm F (2010) Common infections and the risk of stroke. Nat rev Neurol 6(12):681–694. doi:10.1038/nrneurol.2010.163

    Article  PubMed  Google Scholar 

  • Greenhalgh AD, Galea J, Denes A, Tyrrell PJ, Rothwell NJ (2010) Rapid brain penetration of interleukin-1 receptor antagonist in rat cerebral ischaemia: pharmacokinetics, distribution, protection. Br J Pharmacol 160(1):153–159. doi:10.1111/j.1476-5381.2010.00684.x

    Article  PubMed  CAS  Google Scholar 

  • Gui T, Shimokado A, Sun Y, Akasaka T, Muragaki Y (2012) Diverse roles of macrophages in atherosclerosis: from inflammatory biology to biomarker discovery. Mediat Inflamm 2012:14. doi:10.1155/2012/693083

    Article  CAS  Google Scholar 

  • Gustavsson C, Agardh C-D, Zetterqvist AV, Nilsson J, Agardh E, Gomez MF (2010) Vascular cellular adhesion molecule-1 (VCAM-1) expression in mice retinal vessels is affected by both hyperglycemia and hyperlipidemia. PLoS One 5(9):e12699

    Article  PubMed  CAS  Google Scholar 

  • Haeusler KG, Schmidt WU, Fohring F, Meisel C, Helms T, Jungehulsing GJ, Nolte CH, Schmolke K, Wegner B, Meisel A, Dirnagl U, Villringer A, Volk HD (2008) Cellular immunodepression preceding infectious complications after acute ischemic stroke in humans. Cerebrovasc Dis 25(1–2):50–58. doi:10.1159/000111499

    Article  PubMed  CAS  Google Scholar 

  • Hajat C, Heuschmann PU, Coshall C, Padayachee S, Chambers J, Rudd AG, Wolfe CD (2011) Incidence of aetiological subtypes of stroke in a multi-ethnic population based study: the South London Stroke Register. J Neurol Neurosurg Psychiatry 82(5):527–533. doi:10.1136/jnnp.2010.222919

    Article  PubMed  Google Scholar 

  • Hankey GJ (2006) Potential new risk factors for ischemic stroke: what is their potential? Stroke j cereb circ 37(8):2181–2188. doi:10.1161/01.STR.0000229883.72010.e4

    Article  Google Scholar 

  • Hansson GK, Libby P (2006) The immune response in atherosclerosis: a double-edged sword. Nat Rev Immunol 6(7):508–519

    Article  PubMed  CAS  Google Scholar 

  • Hatashita T, Ito M, Miyaoka M, Ishii S (1990) Chronological alterations of regional cerebral blood flow, glucose utilization, and edema formation after focal ischemia in hypertensive and normotensive rats. Significance of hypertension. Adv Neurol 52:29–37

    PubMed  CAS  Google Scholar 

  • Hazeldine J, Hampson P, Lord JM (2012) Reduced release and binding of perforin at the immunological synapse underlies the age-related decline in natural killer cell cytotoxicity. Aging Cell 11(5):751–759

    Article  PubMed  CAS  Google Scholar 

  • Heart Protection Study Collaborative Group, Emberson J, Bennett D, Link E, Parish S, Danesh J, Armitage J, Collins R (2011) C-reactive protein concentration and the vascular benefits of statin therapy: an analysis of 20,536 patients in the Heart Protection Study. Lancet 377:469–476

    Article  Google Scholar 

  • Heo JH, Lucero J, Abumiya T, Koziol JA, Copeland BR, del Zoppo GJ (1999) Matrix metalloproteinases increase very early during experimental focal cerebral ischemia. J Cereb Blood Flow Metab 19(6):624–633

    Article  PubMed  CAS  Google Scholar 

  • Herman JP (2012) Introduction: stress and neurological disease. Exp Neurol 233(1):1–2. doi:10.1016/j.expneurol.2011.12.041

    Article  PubMed  Google Scholar 

  • Horstmann S, Kalb P, Koziol J, Gardner H, Wagner S (2003) Profiles of matrix metalloproteinases, their inhibitors, and laminin in stroke patients: influence of different therapies. Stroke j cereb circ 34(9):2165–2170

    Article  Google Scholar 

  • Hug A, Dalpke A, Wieczorek N, Giese T, Lorenz A, Auffarth G, Liesz A, Veltkamp R (2009) Infarct volume is a major determiner of post-stroke immune cell function and susceptibility to infection. Stroke j cereb circ 40(10):3226–3232. doi:10.1161/STROKEAHA.109.557967

    Article  Google Scholar 

  • Iadecola C, Anrather J (2011) The immunology of stroke: from mechanisms to translation. Nat med 17(7):796–808. doi:10.1038/nm.2399

    Article  PubMed  CAS  Google Scholar 

  • Jian LK, Rosenberg GA (2005) Matrix metalloproteinases and free radicals in cerebral ischemia. Free Radic Biol Med 39(1):71–80

    Article  CAS  Google Scholar 

  • Kamezaki Y, Katsuura S, Kuwano Y, Tanahashi T, Rokutan K (2012) Circulating cytokine signatures in healthy medical students exposed to academic examination stress. Psychophysiology 49(7):991–997

    Article  PubMed  Google Scholar 

  • Kammersgaard LP, Jorgensen HS, Reith J, Nakayama H, Houth JG, Weber UJ, Pedersen PM, Olsen TS (2001) Early infection and prognosis after acute stroke: the Copenhagen Stroke Study. J stroke cerebrovasc dis: off j Natl Stroke Assoc 10(5):217–221. doi:10.1053/jscd.2001.30366

    Article  CAS  Google Scholar 

  • Katsnelson M, Rundek T (2011) Obesity paradox and stroke: noticing the (fat) man behind the curtain. Stroke j cereb circ 42(12):3331–3332

    Article  Google Scholar 

  • Katzan IL, Cebul RD, Husak SH, Dawson NV, Baker DW (2003) The effect of pneumonia on mortality among patients hospitalized for acute stroke. Neurology 60(4):620–625

    Article  PubMed  CAS  Google Scholar 

  • Kim K-A, Gu W, Lee I-A, Joh E-H, Kim D-H (2012) High Fat diet-induced Gut microbiota exacerbates inflammation and obesity in mice via the TLR4 signaling pathway. PLoS One 7(10):e47713

    Article  PubMed  CAS  Google Scholar 

  • Kleemann R, Zadelaar S, Kooistra T (2008) Cytokines and atherosclerosis: a comprehensive review of studies in mice. Cardiovasc Res 79(3):360–376. doi:10.1093/cvr/cvn120

    Article  PubMed  CAS  Google Scholar 

  • Klingenberg R, Hansson GK (2009) Treating inflammation in atherosclerotic cardiovascular disease: emerging therapies. Eur Hear J 30(23):2838–2844. doi:10.1093/eurheartj/ehp477

    Article  CAS  Google Scholar 

  • Kovacs KJ, Elenkov IJ (1995) Differential dependence of ACTH secretion induced by various cytokines on the integrity of the paraventricular nucleus. J Neuroendocrinol 7(1):15–23

    Article  PubMed  CAS  Google Scholar 

  • Kozak W, Kozak A, Johnson MH, Elewa HF, Fagan SC (2008) Vascular protection with candesartan after experimental acute stroke in hypertensive rats: a dose–response study. J Pharmacol Exp Ther 326(3):773–782. doi:10.1124/jpet.108.139618

    Article  PubMed  CAS  Google Scholar 

  • Krupinski J, Kaluza J, Kumar P, Kumar S, Wang JM (1994) Role of angiogenesis in patients with cerebral ischemic stroke. Stroke j cereb circ 25(9):1794–1798

    Article  CAS  Google Scholar 

  • Kumari R, Willing LB, Krady JK, Vannucci SJ, Simpson IA (2007) Impaired wound healing after cerebral hypoxia-ischemia in the diabetic mouse. J Cereb Blood Flow Metab 27(4):710–718

    PubMed  CAS  Google Scholar 

  • Kumari R, Willing LB, Patel SD, Baskerville KA, Simpson IA (2011) Increased cerebral matrix metalloprotease-9 activity is associated with compromised recovery in the diabetic db/db mouse following a stroke. J Neurochem 119(5):1029–1040

    Article  PubMed  CAS  Google Scholar 

  • Kumari R, Willing LB, Patel SD, Krady JK, Zavadoski WJ, Gibbs EM, Vannucci SJ, Simpson IA (2010) The PPAR-gamma agonist, darglitazone, restores acute inflammatory responses to cerebral hypoxia-ischemia in the diabetic ob/ob mouse. J Cereb Blood Flow Metab 30(2):352–360

    Article  PubMed  CAS  Google Scholar 

  • Kusaka I, Kusaka G, Zhou C, Ishikawa M, Nanda A, Granger DN, Zhang JH, Tang J (2004) Role of AT1 receptors and NAD(P)H oxidase in diabetes-aggravated ischemic brain injury. Am J Physiol Heart Circ Physiol 286(6):H2442–H2451. doi:10.1152/ajpheart.01169.2003

    Article  PubMed  CAS  Google Scholar 

  • Ladenvall C, Jood K, Blomstrand C, Nilsson S, Jern C, Ladenvall P (2006) Serum C-reactive protein concentration and genotype in relation to ischemic stroke subtype. Stroke j cereb circ 37(8):2018–2023. doi:10.1161/01.STR.0000231872.86071.68

    Article  CAS  Google Scholar 

  • Laimer M, Kaser S, Kranebitter M, Sandhofer A, Muhlmann G, Schwelberger H, Weiss H, Patsch JR, Ebenbichler CF (2005) Effect of pronounced weight loss on the nontraditional cardiovascular risk marker matrix metalloproteinase-9 in middle-aged morbidly obese women. Int J Obes (Lond) 29(5):498–501

    CAS  Google Scholar 

  • Langdon KD, Clarke J, Corbett D (2011) Long-term exposure to high fat diet is bad for your brain: exacerbation of focal ischemic brain injury. Neuroscience 182:82–87

    Article  PubMed  CAS  Google Scholar 

  • Laskowitz DT, Sheng H, Bart RD, Joyner KA, Roses AD, Warner DS (1997) Apolipoprotein E-deficient mice have increased susceptibility to focal cerebral ischemia. J cereb blood flow metab: off j Int Soc Cereb Blood Flow Metab 17(7):753–758. doi:10.1097/00004647-199707000-00005

    Article  CAS  Google Scholar 

  • Leon B, Lopez-Bravo M, Ardavin C (2007) Monocyte-derived dendritic cells formed at the infection site control the induction of protective T helper 1 responses against leishmania. Immunity 26(4):519–531

    Article  PubMed  CAS  Google Scholar 

  • Lewis DH, Chan DL, Pinheiro D, Armitage-Chan E, Garden OA (2012) The immunopathology of sepsis: pathogen recognition, systemic inflammation, the compensatory anti-inflammatory response, and regulatory T cells. J Vet Intern Med 26(3):457–482

    Article  PubMed  CAS  Google Scholar 

  • Li H, Lelliott C, Hakansson P, Ploj K, Tuneld A, Verolin-Johansson M, Benthem L, Carlsson B, Storlien L, Michaelsson E (2008) Intestinal, adipose, and liver inflammation in diet-induced obese mice. Metabolism 57(12):1704–1710

    Article  PubMed  CAS  Google Scholar 

  • Lindsberg PJ, Carpen O, Paetau A, Karjalainen-Lindsberg ML, Kaste M (1996) Endothelial ICAM-1 expression associated with inflammatory cell response in human ischemic stroke. Circulation 94(5):939–945

    Article  PubMed  CAS  Google Scholar 

  • Liu F, Yuan R, Benashski SE, McCullough LD (2009) Changes in experimental stroke outcome across the life span. J cereb blood flow metab: off j Int Soc Cereb Blood Flow Metab 29(4):792–802. doi:10.1038/jcbfm.2009.5

    Article  CAS  Google Scholar 

  • Liu Y, Liu T, McCarron RM, Spatz M, Feuerstein G, Hallenbeck JM, Siren AL (1996) Evidence for activation of endothelium and monocytes in hypertensive rats. Am J Physiol Heart Circ Physiol 270(6):H2125–H2131

    CAS  Google Scholar 

  • Lord JM, Butcher S, Killampali V, Lascelles D, Salmon M (2001) Neutrophil ageing and immunesenescence. Mech Ageing Dev 122(14):1521–1535

    Article  PubMed  CAS  Google Scholar 

  • Macko RF, Ameriso SF, Barndt R, Clough W, Weiner JM, Fisher M (1996) Precipitants of brain infarction. Roles of preceding infection/inflammation and recent psychological stress. Stroke j cereb circ 27(11):1999–2004

    Article  CAS  Google Scholar 

  • Madrigal JL, Caso JR, de Cristobal J, Cardenas A, Leza JC, Lizasoain I, Lorenzo P, Moro MA (2003) Effect of subacute and chronic immobilisation stress on the outcome of permanent focal cerebral ischaemia in rats. Brain res 979(1–2):137–145

    Article  PubMed  CAS  Google Scholar 

  • Mangat R, Su J, Scott PG, Russell JC, Vine DF, Proctor SD (2007) Chylomicron and apoB48 metabolism in the JCR:LA corpulent rat, a model for the metabolic syndrome. Biochem Soc Trans 35(Pt 3):477–481

    PubMed  CAS  Google Scholar 

  • Mariotti M, Castiglioni S, Bernardini D, Maier J (2006) Iterleukin 1 alpha is a marker of endothelial cellular senescent. Immun Ageing 3(1):4

    Article  PubMed  CAS  Google Scholar 

  • Mariucci G, Taha E, Tantucci M, Spaccatini C, Tozzi A, Ambrosini MV (2011) Intravenous administration of pravastatin immediately after middle cerebral artery occlusion reduces cerebral oedema in spontaneously hypertensive rats. Eur J Pharmacol 660(2–3):381–386. doi:10.1016/j.ejphar.2011.04.002

    Article  PubMed  CAS  Google Scholar 

  • Markus HS, Hunt B, Palmer K, Enzinger C, Schmidt H, Schmidt R (2005) Markers of endothelial and hemostatic activation and progression of cerebral white matter hyperintensities: longitudinal results of the Austrian Stroke Prevention Study. Stroke j cereb circ 36(7):1410–1414. doi:10.1161/01.STR.0000169924.60783.d4

    Article  CAS  Google Scholar 

  • Marnane M, Merwick A, Sheehan OC, Hannon N, Foran P, Grant T, Dolan E, Moroney J, Murphy S, O’Rourke K, O’Malley K, O’Donohoe M, McDonnell C, Noone I, Barry M, Crowe M, Kavanagh E, O’Connell M, Kelly PJ (2012) Carotid plaque inflammation on 18F-fluorodeoxyglucose positron emission tomography predicts early stroke recurrence. Ann Neurol 71(5):709–718. doi:10.1002/ana.23553

    Article  PubMed  Google Scholar 

  • Marvar PJ, Thabet SR, Guzik TJ, Lob HE, McCann LA, Weyand C, Gordon FJ, Harrison DG (2010) Central and peripheral mechanisms of T-lymphocyte activation and vascular inflammation produced by angiotensin II-induced hypertension. Circ Res 107(2):263–270. doi:10.1161/circresaha.110.217299

    Article  PubMed  CAS  Google Scholar 

  • Maslanik T, Bernstein-Hanley I, Helwig B, Fleshner M (2012) The impact of acute-stressor exposure on splenic innate immunity: a gene expression analysis. Brain behav immun 26(1):142–149

    Article  PubMed  CAS  Google Scholar 

  • McColl BW, Allan SM, Rothwell NJ (2009) Systemic infection, inflammation and acute ischemic stroke. Neuroscience 158(3):1049–1061. doi:10.1016/j.neuroscience.2008.08.019

    Article  PubMed  CAS  Google Scholar 

  • McColl BW, Rose N, Robson FH, Rothwell NJ, Lawrence CB (2010a) Increased brain microvascular MMP-9 and incidence of haemorrhagic transformation in obese mice after experimental stroke. J cereb blood flow metab: off j Int Soc Cereb Blood Flow Metab 30(2):267–272. doi:10.1038/jcbfm.2009.217

    Article  CAS  Google Scholar 

  • McColl BW, Rose N, Robson FH, Rothwell NJ, Lawrence CB (2010b) Increased brain microvascular MMP-9 and incidence of haemorrhagic transformation in obese mice after experimental stroke. J Cereb Blood Flow Metab 30(2):267–272

    Article  PubMed  CAS  Google Scholar 

  • McColl BW, Rothwell NJ, Allan SM (2007) Systemic inflammatory stimulus potentiates the acute phase and CXC chemokine responses to experimental stroke and exacerbates brain damage via interleukin-1- and neutrophil-dependent mechanisms. J neurosci: off j Soc Neurosci 27(16):4403–4412. doi:10.1523/JNEUROSCI.5376-06.2007

    Article  CAS  Google Scholar 

  • McColl BW, Rothwell NJ, Allan SM (2008) Systemic inflammation alters the kinetics of cerebrovascular tight junction disruption after experimental stroke in mice. J neurosci: off j Soc Neurosci 28(38):9451–9462. doi:10.1523/JNEUROSCI.2674-08.2008

    Article  CAS  Google Scholar 

  • McEwen BS (2000) The neurobiology of stress: from serendipity to clinical relevance. Brain res 886(1–2):172–189

    Article  PubMed  CAS  Google Scholar 

  • Miller GE, Cohen S, Herbert TB (1999) Pathways linking major depression and immunity in ambulatory female patients. Psychosom Med 61(6):850–860

    PubMed  CAS  Google Scholar 

  • Moreno PR, Falk E, Palacios IF, Newell JB, Fuster V, Fallon JT (1994) Macrophage infiltration in acute coronary syndromes. Implications for plaque rupture. Circulation 90(2):775–778. doi:10.1161/01.cir.90.2.775

    Article  PubMed  CAS  Google Scholar 

  • Moreno PR, Murcia AM, Palacios IF, Leon MN, Bernardi VH, Fuster V, Fallon JT (2000) Coronary composition and macrophage infiltration in atherectomy specimens from patients with diabetes mellitus. Circulation 102(18):2180–2184. doi:10.1161/01.cir.102.18.2180

    Article  PubMed  CAS  Google Scholar 

  • Morgan TE, Xie Z, Goldsmith S, Yoshida T, Lanzrein AS, Stone D, Rozovsky I, Perry G, Smith MA, Finch CE (1999) The mosaic of brain glial hyperactivity during normal ageing and its attenuation by food restriction. Neuroscience 89(3):687–699

    Article  PubMed  CAS  Google Scholar 

  • Moustafa RR, Izquierdo-Garcia D, Fryer TD, Graves MJ, Rudd JH, Gillard JH, Weissberg PL, Baron JC, Warburton EA (2010) Carotid plaque inflammation is associated with cerebral microembolism in patients with recent transient ischemic attack or stroke: a pilot study. Circ Cardiovasc imaging 3(5):536–541. doi:10.1161/CIRCIMAGING.110.938225

    Article  PubMed  Google Scholar 

  • Muhammad S, Haasbach E, Kotchourko M, Strigli A, Krenz A, Ridder DA, Vogel AB, Marti HH, Al-Abed Y, Planz O, Schwaninger M (2011) Influenza virus infection aggravates stroke outcome. Stroke j cereb circ 42(3):783–791. doi:10.1161/STROKEAHA.110.596783

    Article  CAS  Google Scholar 

  • Mulcahy NJ, Ross J, Rothwell NJ, Loddick SA (2003) Delayed administration of interleukin-1 receptor antagonist protects against transient cerebral ischaemia in the rat. Br J Pharmacol 140(3):471–476

    Article  PubMed  CAS  Google Scholar 

  • Munhoz CD, Garcia-Bueno B, Madrigal JL, Lepsch LB, Scavone C, Leza JC (2008) Stress-induced neuroinflammation: mechanisms and new pharmacological targets. Braz j med biol res = Rev bras pesq med biol / Soc Bras Biofisica [et al] 41(12):1037–1046

    CAS  Google Scholar 

  • Munhoz CD, Sorrells SF, Caso JR, Scavone C, Sapolsky RM (2010) Glucocorticoids exacerbate lipopolysaccharide-induced signaling in the frontal cortex and hippocampus in a dose-dependent manner. J neurosci: off j Soc Neurosci 30(41):13690–13698. doi:10.1523/JNEUROSCI.0303-09.2010

    Article  CAS  Google Scholar 

  • Nagai N, Van Hoef B, Lijnen HR (2007) Plasminogen activator inhibitor-1 contributes to the deleterious effect of obesity on the outcome of thrombotic ischemic stroke in mice. J Thromb Haemost 5(8):1726–1731

    Article  PubMed  CAS  Google Scholar 

  • Nair A, Bonneau RH (2006) Stress-induced elevation of glucocorticoids increases microglia proliferation through NMDA receptor activation. J Neuroimmunol 171(1–2):72–85. doi:10.1016/j.jneuroim.2005.09.012

    Article  PubMed  CAS  Google Scholar 

  • Nakashima Y, Raines EW, Plump AS, Breslow JL, Ross R (1998) Upregulation of VCAM-1 and ICAM-1 at atherosclerosis-prone sites on the endothelium in the ApoE-deficient mouse. Arterioscler Thromb Vasc Biol 18(5):842–851. doi:10.1161/01.atv.18.5.842

    Article  PubMed  CAS  Google Scholar 

  • Nighoghossian N, Wiart M, Cakmak S, Berthezene Y, Derex L, Cho TH, Nemoz C, Chapuis F, Tisserand GL, Pialat JB, Trouillas P, Froment JC, Hermier M (2007) Inflammatory response after ischemic stroke: a USPIO-enhanced MRI study in patients. Stroke j cereb circ 38(2):303–307. doi:10.1161/01.STR.0000254548.30258.f2

    Article  Google Scholar 

  • O’Donnell MJ, Xavier D, Liu L, Zhang H, Chin SL, Rao-Melacini P, Rangarajan S, Islam S, Pais P, McQueen MJ, Mondo C, Damasceno A, Lopez-Jaramillo P, Hankey GJ, Dans AL, Yusoff K, Truelsen T, Diener H-C, Sacco RL, Ryglewicz D, Czlonkowska A, Weimar C, Wang X, Yusuf S (2010) Risk factors for ischaemic and intracerebral haemorrhagic stroke in 22 countries (the INTERSTROKE study): a case–control study. Lancet 376(9735):112–123

    Article  PubMed  Google Scholar 

  • Ohmura K, Ishimori N, Ohmura Y, Tokuhara S, Nozawa A, Horii S, Andoh Y, Fujii S, Iwabuchi K, Onoe K, Tsutsui H (2010) Natural killer T cells are involved in adipose tissues inflammation and glucose intolerance in diet-induced obese mice. Arterioscler Thromb Vasc Biol 30(2):193–199. doi:10.1161/atvbaha.109.198614

    Article  PubMed  CAS  Google Scholar 

  • Oki I, Nakamura Y, Okamura T, Okayama A, Hayakawa T, Kita Y, Ueshima H (2006) Body mass index and risk of stroke mortality among a random sample of Japanese adults: 19-year follow-up of NIPPON DATA80. Cerebrovasc Dis 22(5–6):409–415

    Article  PubMed  Google Scholar 

  • Olsen TS, Dehlendorff C, Petersen HG, Andersen KK (2008) Body mass index and poststroke mortality. Neuroepidemiology 30(2):93–100

    Article  PubMed  Google Scholar 

  • Olsson T (1990) Urinary free cortisol excretion shortly after ischaemic stroke. J intern med 228(2):177–181

    Article  PubMed  CAS  Google Scholar 

  • Ovbiagele B, Nguyen-Huynh MN (2011) Stroke epidemiology: advancing our understanding of disease mechanism and therapy. Neurother: j Am Soc Exp NeuroTher 8(3):319–329. doi:10.1007/s13311-011-0053-1

    Article  Google Scholar 

  • Packard RR, Lichtman AH, Libby P (2009) Innate and adaptive immunity in atherosclerosis. Semin Immunopathol 31(1):5–22. doi:10.1007/s00281-009-0153-8

    Article  PubMed  CAS  Google Scholar 

  • Paganini-Hill A, Lozano E, Fischberg G, Perez Barreto M, Rajamani K, Ameriso SF, Heseltine PN, Fisher M (2003) Infection and risk of ischemic stroke: differences among stroke subtypes. Stroke j cereb circ 34(2):452–457

    Article  CAS  Google Scholar 

  • Pan W, Hsuchou H, Jayaram B, Khan RS, Huang EY-K, Wu X, Chen C, Kastin AJ (2012) Leptin action on nonneuronal cells in the CNS: potential clinical applications. Ann N Y Acad Sci 1264(1):64–71

    Article  PubMed  CAS  Google Scholar 

  • Pappata S, Levasseur M, Gunn RN, Myers R, Crouzel C, Syrota A, Jones T, Kreutzberg GW, Banati RB (2000) Thalamic microglial activation in ischemic stroke detected in vivo by PET and [11C]PK1195. Neurology 55(7):1052–1054

    Article  PubMed  CAS  Google Scholar 

  • Park S, Kim DS, Kang S, Kwon DY (2011) Ischemic hippocampal cell death induces glucose dysregulation by attenuating glucose-stimulated insulin secretion which is exacerbated by a high fat diet. Life Sci 88(17–18):766–773

    Article  PubMed  CAS  Google Scholar 

  • Pinteaux E, Rothwell NJ, Boutin H (2006) Neuroprotective actions of endogenous interleukin-1 receptor antagonist (IL-1ra) are mediated by glia. Glia 53(5):551–556

    Article  PubMed  Google Scholar 

  • Pistell PJ, Morrison CD, Gupta S, Knight AG, Keller JN, Ingram DK, Bruce-Keller AJ (2010) Cognitive impairment following high fat diet consumption is associated with brain inflammation. J Neuroimmunol 219(1–2):25–32

    Article  PubMed  CAS  Google Scholar 

  • Porritt MJ, Chen M, Rewell SS, Dean RG, Burrell LM, Howells DW (2010) ACE inhibition reduces infarction in normotensive but not hypertensive rats: correlation with cortical ACE activity. J cereb blood flow metab: off j Int Soc Cereb Blood Flow Metab 30(8):1520–1526. doi:10.1038/jcbfm.2010.57

    Article  CAS  Google Scholar 

  • Pradillo JM, Denes A, Greenhalgh AD, Boutin H, Drake C, McColl BW, Barton E, Proctor SD, Russell JC, Rothwell NJ, Allan SM (2012) Delayed administration of interleukin-1 receptor antagonist reduces ischemic brain damage and inflammation in comorbid rats. J cereb blood flow metab: off j Int Soc Cereb Blood Flow Metab 32(9):1810–1819. doi:10.1038/jcbfm.2012.101

    Article  CAS  Google Scholar 

  • Prager M, Turel Z, Speidl WS, Zorn G, Kaun C, Niessner A, Heinze G, Huk I, Maurer G, Huber K, Wojta J (2002) Chlamydia pneumoniae in carotid artery atherosclerosis: a comparison of its presence in atherosclerotic plaque, healthy vessels, and circulating leukocytes from the same individuals. Stroke j cereb circ 33(12):2756–2761

    Article  Google Scholar 

  • Price CJ, Menon DK, Peters AM, Ballinger JR, Barber RW, Balan KK, Lynch A, Xuereb JH, Fryer T, Guadagno JV, Warburton EA (2004) Cerebral neutrophil recruitment, histology, and outcome in acute ischemic stroke: an imaging-based study. Stroke j cereb circ 35(7):1659–1664. doi:10.1161/01.STR.0000130592.71028.92

    Article  CAS  Google Scholar 

  • Purushothaman KR, Krishnan P, Purushothaman M, Wiley J, Alviar CL, Ruiz FJ, Zubatov Y, Kini AS, Sharma SK, Fuster V, Moreno PR (2012) Expression of angiotensin-converting enzyme 2 and its end product angiotensin 1–7 is increased in diabetic atheroma: implications for inflammation and neovascularization. Cardiovasc Pathol (0)

  • Radlinska BA, Ghinani SA, Lyon P, Jolly D, Soucy JP, Minuk J, Schirrmacher R, Thiel A (2009) Multimodal microglia imaging of fiber tracts in acute subcortical stroke. Ann Neurol 66(6):825–832. doi:10.1002/ana.21796

    Article  PubMed  Google Scholar 

  • Rallidis LS, Zolindaki MG, Vikelis M, Kaliva K, Papadopoulos C, Kremastinos DT (2009) Elevated soluble intercellular adhesion molecule-1 levels are associated with poor short-term prognosis in middle-aged patients with acute ischaemic stroke. Int J Cardiol 132(2):216–220. doi:10.1016/j.ijcard.2007.11.031

    Article  PubMed  Google Scholar 

  • Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, Koenig W, Libby P, Lorenzatti AJ, MacFadyen JG, Nordestgaard BG, Shepherd J, Willerson JT, Glynn RJ (2008) Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 359(21):2195–2207. doi:10.1056/NEJMoa0807646

    Article  PubMed  CAS  Google Scholar 

  • Rizk NN, Myatt-Jones J, Rafols J, Dunbar JC (2007) Insulin like growth factor-1 (IGF-1) decreases ischemia-reperfusion induced apoptosis and necrosis in diabetic rats. Endocrine 31(1):66–71

    Article  PubMed  CAS  Google Scholar 

  • Romanic AM, White RF, Arleth AJ, Ohlstein EH, Barone FC (1998) Matrix metalloproteinase expression increases after cerebral focal ischemia in rats: inhibition of matrix metalloproteinase-9 reduces infarct size. Stroke j cereb circ 29(5):1020–1030

    Article  CAS  Google Scholar 

  • Roquer J, Cuadrado-Godia E, Giralt-Steinthauer E, Jimena S, Jimenez-Conde J, Martinez-Rodriguez JE, Ois A, Rodriguez-Campello A (2012) Previous infection and stroke: a prospective study. Cerebrovasc Dis 33(4):310–315. doi:10.1159/000335306

    Article  PubMed  Google Scholar 

  • Rosell A, Ortega-Aznar A, Alvarez-Sabin J, Fernandez-Cadenas I, Ribo M, Molina CA, Lo EH, Montaner J (2006) Increased brain expression of matrix metalloproteinase-9 after ischemic and hemorrhagic human stroke. Stroke j cereb circ 37(6):1399–1406

    Article  CAS  Google Scholar 

  • Rosenberg GA, Estrada EY, Dencoff JE (1998) Matrix metalloproteinases and TIMPs are associated with blood–brain barrier opening after reperfusion in rat brain. Stroke j cereb circ 29(10):2189–2195

    Article  CAS  Google Scholar 

  • Rudd JH, Narula J, Strauss HW, Virmani R, Machac J, Klimas M, Tahara N, Fuster V, Warburton EA, Fayad ZA, Tawakol AA (2010) Imaging atherosclerotic plaque inflammation by fluorodeoxyglucose with positron emission tomography: ready for prime time? J Am Coll Cardiol 55(23):2527–2535. doi:10.1016/j.jacc.2009.12.061

    Article  PubMed  Google Scholar 

  • Ryu WS, Lee SH, Kim CK, Kim BJ, Yoon BW (2011) Body mass index, initial neurological severity and long-term mortality in ischemic stroke. Cerebrovasc Dis 32(2):170–176

    Article  PubMed  Google Scholar 

  • Sacco RL, Benjamin EJ, Broderick JP, Dyken M, Easton JD, Feinberg WM, Goldstein LB, Gorelick PB, Howard G, Kittner SJ, Manolio TA, Whisnant JP, Wolf PA (1997) Risk factors. Stroke j cereb circ 28(7):1507–1517. doi:10.1161/01.str.28.7.1507

    Article  CAS  Google Scholar 

  • Sairanen T, Carpen O, Karjalainen-Lindsberg ML, Paetau A, Turpeinen U, Kaste M, Lindsberg PJ (2001) Evolution of cerebral tumor necrosis factor-alpha production during human ischemic stroke. Stroke j cereb circ 32(8):1750–1758

    Article  CAS  Google Scholar 

  • Saleh A, Schroeter M, Jonkmanns C, Hartung HP, Modder U, Jander S (2004) In vivo MRI of brain inflammation in human ischaemic stroke. Brain: j neurol 127(Pt 7):1670–1677. doi:10.1093/brain/awh191

    Article  Google Scholar 

  • Sander D, Poppert H, Sander K, Etgen T (2011) The role of intima-media-thickness, ankle-brachial-index and inflammatory biochemical parameters for stroke risk prediction: a systematic review. Eur J Neurol 19(4):544–e536

    Article  PubMed  Google Scholar 

  • Sander D, Winbeck K, Klingelhofer J, Etgen T, Conrad B (2004) Progression of early carotid atherosclerosis is only temporarily reduced after antibiotic treatment of Chlamydia pneumoniae seropositivity. Circulation 109(8):1010–1015. doi:10.1161/01.CIR.0000117232.30832.EC

    Article  PubMed  CAS  Google Scholar 

  • Sandercock PA, Soane T (2011) Corticosteroids for acute ischaemic stroke. Cochrane Database Syst Rev (9):CD000064. doi:10.1002/14651858.CD000064.pub2

  • Sanz-Rosa D, Oubina MP, Cediel E, de las Heras N, Vegazo O, Jimenez J, Lahera V, Cachofeiro V (2005) Effect of AT1 receptor antagonism on vascular and circulating inflammatory mediators in SHR: role of NF-kappaB/IkappaB system. Heart Circ Physiol 288(1):H111–H115. doi:10.1152/ajpheart.01061.2003

    Article  CAS  Google Scholar 

  • Scarpellini E, Tack J (2012) Obesity and metabolic syndrome: an inflammatory condition. Dig dis (Basel, Switzerland) 30(2):148–153

    Article  CAS  Google Scholar 

  • Schieffer B, Schieffer E, Hilfiker-Kleiner D, Hilfiker A, Kovanen PT, Kaartinen M, Nussberger J, Harringer W, Drexler H (2000) Expression of angiotensin II and interleukin 6 in human coronary atherosclerotic plaques. Circulation 101(12):1372–1378. doi:10.1161/01.cir.101.12.1372

    Article  PubMed  CAS  Google Scholar 

  • Schmid-Schonbein GW, Seiffge D, DeLano FA, Shen K, Zweifach BW (1991) Leukocyte counts and activation in spontaneously hypertensive and normotensive rats. Hypertension 17(3):323–330. doi:10.1161/01.hyp.17.3.323

    Article  PubMed  CAS  Google Scholar 

  • Schmidt R, Schmidt H, Pichler M, Enzinger C, Petrovic K, Niederkorn K, Horner S, Ropele S, Watzinger N, Schumacher M, Berghold A, Kostner GM, Fazekas F (2006) C-reactive protein, carotid atherosclerosis, and cerebral small-vessel disease: results of the Austrian Stroke Prevention Study. Stroke j cereb circ 37(12):2910–2916. doi:10.1161/01.STR.0000248768.40043.f9

    Article  CAS  Google Scholar 

  • Selmeczy Z, Vizi ES, Csoka B, Pacher P, Hasko G (2008) Role of nonsynaptic communication in regulating the immune response. Neurochem Int 52(1–2):52–59. doi:10.1016/j.neuint.2007.06.001

    Article  PubMed  CAS  Google Scholar 

  • Selvamani A, Sohrabji F (2010a) The neurotoxic effects of estrogen on ischemic stroke in older female rats is associated with age-dependent loss of insulin-like growth factor-1. J neurosci: off j Soc Neurosci 30(20):6852–6861. doi:10.1523/JNEUROSCI.0761-10.2010

    Article  CAS  Google Scholar 

  • Selvamani A, Sohrabji F (2010b) Reproductive age modulates the impact of focal ischemia on the forebrain as well as the effects of estrogen treatment in female rats. Neurobiol aging 31(9):1618–1628. doi:10.1016/j.neurobiolaging.2008.08.014

    Article  PubMed  CAS  Google Scholar 

  • Shapira S, Sapir M, Wengier A, Grauer E, Kadar T (2002) Aging has a complex effect on a rat model of ischemic stroke. Brain res 925(2):148–158

    Article  PubMed  CAS  Google Scholar 

  • Sierra C, Coca A, Schiffrin EL (2011) Vascular mechanisms in the pathogenesis of stroke. Curr hypertens rep 13(3):200–207. doi:10.1007/s11906-011-0195-x

    Article  PubMed  CAS  Google Scholar 

  • Smith CJ, Emsley HC, Gavin CM, Georgiou RF, Vail A, Barberan EM, del Zoppo GJ, Hallenbeck JM, Rothwell NJ, Hopkins SJ, Tyrrell PJ (2004) Peak plasma interleukin-6 and other peripheral markers of inflammation in the first week of ischaemic stroke correlate with brain infarct volume, stroke severity and long-term outcome. BMC Neurol 4:2. doi:10.1186/1471-2377-4-2

    Article  PubMed  Google Scholar 

  • Smith CJ, Emsley HC, Udeh CT, Vail A, Hoadley ME, Rothwell NJ, Tyrrell PJ, Hopkins SJ (2012) Interleukin-1 receptor antagonist reverses stroke-associated peripheral immune suppression. Cytokine 58(3):384–389. doi:10.1016/j.cyto.2012.02.016

    Article  PubMed  CAS  Google Scholar 

  • Solana R, Mariani E (2000) NK and NK/T cells in human senescence. Vaccine 18(16):1613–1620

    Article  PubMed  CAS  Google Scholar 

  • Sorrells SF, Caso JR, Munhoz CD, Sapolsky RM (2009) The stressed CNS: when glucocorticoids aggravate inflammation. Neuron 64(1):33–39. doi:10.1016/j.neuron.2009.09.032

    Article  PubMed  CAS  Google Scholar 

  • Sorrells SF, Sapolsky RM (2007) An inflammatory review of glucocorticoid actions in the CNS. Brain behav immun 21(3):259–272. doi:10.1016/j.bbi.2006.11.006

    Article  PubMed  CAS  Google Scholar 

  • Srinivasan D, Yen JH, Joseph DJ, Friedman W (2004) Cell type-specific interleukin-1beta signaling in the CNS. J neurosci: off j Soc Neurosci 24(29):6482–6488. doi:10.1523/JNEUROSCI.5712-03.2004

    Article  CAS  Google Scholar 

  • Stelzer I, Zelzer S, Raggam RB, Pruller F, Truschnig-Wilders M, Meinitzer A, Schnedl WJ, Horejsi R, Moller R, Weghuber D, Reeves G, Postolache TT, Mangge H (2012) Link between leptin and interleukin-6 levels in the initial phase of obesity related inflammation. Transl Res 159(2):118–124

    Article  PubMed  CAS  Google Scholar 

  • Strazzullo P, D’Elia L, Cairella G, Garbagnati F, Cappuccio FP, Scalfi L (2010) Excess body weight and incidence of stroke: meta-analysis of prospective studies with 2 million participants. Stroke j cereb circ 41(5):e418–e426

    Article  Google Scholar 

  • Stroemer RP, Rothwell NJ (1997) Cortical protection by localized striatal injection of IL-1ra following cerebral ischemia in the rat. J cereb blood flow metab: off j Int Soc Cereb Blood Flow Metab 17(6):597–604

    Article  CAS  Google Scholar 

  • Sugama S, Fujita M, Hashimoto M, Conti B (2007) Stress induced morphological microglial activation in the rodent brain: involvement of interleukin-18. Neuroscience 146(3):1388–1399. doi:10.1016/j.neuroscience.2007.02.043

    Article  PubMed  CAS  Google Scholar 

  • Sugama S, Takenouchi T, Fujita M, Kitani H, Hashimoto M (2010) Cold stress induced morphological microglial activation and increased IL-1Î2 expression in astroglial cells in rat brain. J Neuroimmunol 233(1–2):29–36

    PubMed  Google Scholar 

  • Sugo N, Hurn PD, Morahan MB, Hattori K, Traystman RJ, DeVries AC (2002) Social stress exacerbates focal cerebral ischemia in mice. Stroke j cereb circ 33(6):1660–1664

    Article  Google Scholar 

  • Sun S, Ji Y, Kersten S, Qi L (2012) Mechanisms of inflammatory responses in obese adipose tissue. Annu Rev Nutr 32:261–286

    Article  PubMed  CAS  Google Scholar 

  • Surtees PG, Wainwright NW, Luben RN, Wareham NJ, Bingham SA, Khaw KT (2008) Psychological distress, major depressive disorder, and risk of stroke. Neurology 70(10):788–794. doi:10.1212/01.wnl.0000304109.18563.81

    Article  PubMed  CAS  Google Scholar 

  • Tahara N, Kai H, Ishibashi M, Nakaura H, Kaida H, Baba K, Hayabuchi N, Imaizumi T (2006) Simvastatin attenuates plaque inflammation: evaluation by fluorodeoxyglucose positron emission tomography. J Am Coll Cardiol 48(9):1825–1831. doi:10.1016/j.jacc.2006.03.069

    Article  PubMed  CAS  Google Scholar 

  • Tarkowski E, Rosengren L, Blomstrand C, Wikkelso C, Jensen C, Ekholm S, Tarkowski A (1995) Early intrathecal production of interleukin-6 predicts the size of brain lesion in stroke. Stroke j cereb circ 26(8):1393–1398

    Article  CAS  Google Scholar 

  • Tawakol A, Migrino RQ, Bashian GG, Bedri S, Vermylen D, Cury RC, Yates D, LaMuraglia GM, Furie K, Houser S, Gewirtz H, Muller JE, Brady TJ, Fischman AJ (2006) In vivo 18F-fluorodeoxyglucose positron emission tomography imaging provides a noninvasive measure of carotid plaque inflammation in patients. J Am Coll Cardiol 48(9):1818–1824. doi:10.1016/j.jacc.2006.05.076

    Article  PubMed  Google Scholar 

  • Terao S, Yilmaz G, Stokes KY, Ishikawa M, Kawase T, Granger DN (2008) Inflammatory and injury responses to ischemic stroke in obese mice. Stroke j cereb circ 39(3):943–950

    Article  Google Scholar 

  • Thaler JP, Yi CX, Schur EA, Guyenet SJ, Hwang BH, Dietrich MO, Zhao X, Sarruf DA, Izgur V, Maravilla KR, Nguyen HT, Fischer JD, Matsen ME, Wisse BE, Morton GJ, Horvath TL, Baskin DG, Tschop MH, Schwartz MW (2012) Obesity is associated with hypothalamic injury in rodents and humans. J Clin Invest 122(1):153–162

    Article  PubMed  CAS  Google Scholar 

  • The Emerging Risk Factors Collaboration, Kaptoge S, Di Angelantonio E, Lowe G, Pepys MB, Thompson SG, Collins R, Danesh J (2010) C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis. Lancet 375:132–140

    Article  PubMed  CAS  Google Scholar 

  • The Global Burden of Disease (2004) WHO http://wwwwhoint/healthinfo/global_burden_disease/GBD_report_2004update_fullpdf

  • Top Ten Causes of Death (2011) WHO http://wwwwhoint/mediacentre/factsheets/fs310_2008pdf

  • Toung TK, Hurn PD, Traystman RJ, Sieber FE (2000) Estrogen decreases infarct size after temporary focal ischemia in a genetic model of type 1 diabetes mellitus. Stroke j cereb circ 31(11):2701–2706

    Article  CAS  Google Scholar 

  • Towfighi A, Ovbiagele B (2009) The impact of body mass index on mortality after stroke. Stroke j cereb circ 40(8):2704–2708

    Article  Google Scholar 

  • Tureyen K, Bowen K, Liang J, Dempsey RJ, Vemuganti R (2011) Exacerbated brain damage, edema and inflammation in type-2 diabetic mice subjected to focal ischemia. J Neurochem 116(4):499–507

    Article  PubMed  CAS  Google Scholar 

  • Tureyen K, Kapadia R, Bowen KK, Satriotomo I, Liang J, Feinstein DL, Vemuganti R (2007) Peroxisome proliferator-activated receptor-gamma agonists induce neuroprotection following transient focal ischemia in normotensive, normoglycemic as well as hypertensive and type-2 diabetic rodents. J Neurochem 101(1):41–56. doi:10.1111/j.1471-4159.2006.04376.x

    Article  PubMed  CAS  Google Scholar 

  • Tuttolomondo A, Di Sciacca R, Di Raimondo D, Serio A, D’Aguanno G, La Placa S, Pecoraro R, Arnao V, Marino L, Monaco S, Natale E, Licata G, Pinto A (2009) Plasma levels of inflammatory and thrombotic/fibrinolytic markers in acute ischemic strokes: relationship with TOAST subtype, outcome and infarct site. J Neuroimmunol 215(1–2):84–89. doi:10.1016/j.jneuroim.2009.06.019

    Article  PubMed  CAS  Google Scholar 

  • Uchida Y, Takeshita K, Yamamoto K, Kikuchi R, Nakayama T, Nomura M, Cheng XW, Egashira K, Matsushita T, Nakamura H, Murohara T (2012) Stress augments insulin resistance and prothrombotic state: role of visceral adipose-derived monocyte chemoattractant protein-1. Diabetes 61(6):1552–1561. doi:10.2337/db11-0828

    Article  PubMed  CAS  Google Scholar 

  • Ueland T, Smedbakken LM, Hallen J, Atar D, Januzzi JL, Halvorsen B, Jensen JK, Aukrust P (2012) Soluble CXCL16 and long-term outcome in acute ischemic stroke. Atherosclerosis 220(1):244–249. doi:10.1016/j.atherosclerosis.2011.10.004

    Article  PubMed  CAS  Google Scholar 

  • Umemura T, Kawamura T, Umegaki H, Mashita S, Kanai A, Sakakibara T, Hotta N, Sobue G (2011) Endothelial and inflammatory markers in relation to progression of ischaemic cerebral small-vessel disease and cognitive impairment: a 6-year longitudinal study in patients with type 2 diabetes mellitus. J Neurol Neurosurg Psychiatry 82(11):1186–1194. doi:10.1136/jnnp.2010.217380

    Article  PubMed  CAS  Google Scholar 

  • Urra X, Cervera A, Obach V, Climent N, Planas AM, Chamorro A (2009) Monocytes are major players in the prognosis and risk of infection after acute stroke. Stroke j cereb circ 40(4):1262–1268. doi:10.1161/STROKEAHA.108.532085

    Article  CAS  Google Scholar 

  • van Dijk EJ, Prins ND, Vermeer SE, Vrooman HA, Hofman A, Koudstaal PJ, Breteler MM (2005) C-reactive protein and cerebral small-vessel disease: the Rotterdam Scan Study. Circulation 112(6):900–905. doi:10.1161/CIRCULATIONAHA.104.506337

    Article  PubMed  CAS  Google Scholar 

  • Vemmos K, Ntaios G, Spengos K, Savvari P, Vemmou A, Pappa T, Manios E, Georgiopoulos G, Alevizaki M (2011) Association between obesity and mortality after acute first-ever stroke: the obesity-stroke paradox. Stroke j cereb circ 42(1):30–36

    Article  Google Scholar 

  • Venketasubramanian N, Rother J, Bhatt DL, Pasquet B, Mas JL, Alberts MJ, Hill MD, Aichner F, Steg PG (2011) Two-year vascular event rates in patients with symptomatic cerebrovascular disease: the REACH registry. Cerebrovasc Dis 32(3):254–260. doi:10.1159/000328650

    Article  PubMed  Google Scholar 

  • Vila N, Filella X, Deulofeu R, Ascaso C, Abellana R, Chamorro A (1999) Cytokine-induced inflammation and long-term stroke functional outcome. J Neurol Sci 162(2):185–188

    Article  PubMed  CAS  Google Scholar 

  • Walkey AJ, Wiener RS, Ghobrial JM, Curtis LH, Benjamin EJ (2011) Incident stroke and mortality associated with new-onset atrial fibrillation in patients hospitalized with severe sepsis. JAMA: j Am Med Assoc 306(20):2248–2254. doi:10.1001/jama.2011.1615

    Article  CAS  Google Scholar 

  • Wang RY, Wang PS, Yang YR (2003) Effect of age in rats following middle cerebral artery occlusion. Gerontology 49(1):27–32

    Article  PubMed  Google Scholar 

  • Wang T, Fu FH, Han B, Zhu M, Yu X, Zhang LM (2009) Aspirin attenuates cerebral ischemic injury in diabetic rats. Exp clin endocrinol diab: off j German Soc Endocrinol German Diab Assoc 117(4):181–185. doi:10.1055/s-0028-1087210

    Article  CAS  Google Scholar 

  • Wardlaw JM, Murray V, Berge E, del Zoppo G, Sandercock P, Lindley RL, Cohen G (2012) Recombinant tissue plasminogen activator for acute ischaemic stroke: an updated systematic review and meta-analysis. Lancet 379(9834):2364–2372. doi:10.1016/S0140-6736(12)60738-7

    Article  PubMed  CAS  Google Scholar 

  • Weimar C, Konig IR, Kraywinkel K, Ziegler A, Diener HC (2004) Age and National Institutes of Health Stroke Scale Score within 6 hours after onset are accurate predictors of outcome after cerebral ischemia: development and external validation of prognostic models. Stroke j cereb circ 35(1):158–162. doi:10.1161/01.STR.0000106761.94985.8B

    Article  CAS  Google Scholar 

  • Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW (2003) Obesity is associated with macrophage accumulation in adipose tissue. J Clin Investig 112(12):1796–1808

    PubMed  CAS  Google Scholar 

  • Westendorp WF, Nederkoorn PJ, Vermeij JD, Dijkgraaf MG, van de Beek D (2011) Post-stroke infection: a systematic review and meta-analysis. BMC Neurol 11:110. doi:10.1186/1471-2377-11-110

    Article  PubMed  Google Scholar 

  • Whiteley W, Jackson C, Lewis S, Lowe G, Rumley A, Sandercock P, Wardlaw J, Dennis M, Sudlow C (2009) Inflammatory markers and poor outcome after stroke: a prospective cohort study and systematic review of interleukin-6. PLoS med 6(9):e1000145. doi:10.1371/journal.pmed.1000145

    Article  PubMed  CAS  Google Scholar 

  • Whitlock G, Lewington S, Sherliker P, Clarke R, Emberson J, Halsey J, Qizilbash N, Collins R, Peto R (2009) Body-mass index and cause-specific mortality in 900 000 adults: collaborative analyses of 57 prospective studies. Lancet 373(9669):1083–1096

    Article  PubMed  Google Scholar 

  • Winbeck K, Poppert H, Etgen T, Conrad B, Sander D (2002) Prognostic relevance of early serial C-reactive protein measurements after first ischemic stroke. Stroke j cereb circ 33(10):2459–2464

    Article  CAS  Google Scholar 

  • Wolf PA, D’Agostino RB, O’Neal MA, Sytkowski P, Kase CS, Belanger AJ, Kannel WB (1992) Secular trends in stroke incidence and mortality. The Framingham Study. Stroke j cereb circ 23(11):1551–1555

    Article  CAS  Google Scholar 

  • Wright CB, Moon Y, Paik MC, Brown TR, Rabbani L, Yoshita M, DeCarli C, Sacco R, Elkind MS (2009) Inflammatory biomarkers of vascular risk as correlates of leukoariosis. Stroke j cereb circ 40(11):3466–3471. doi:10.1161/STROKEAHA.109.559567

    Article  CAS  Google Scholar 

  • Yang Y, Santamaria P (2006) Lessons on autoimmune diabetes from animal models. Clin Sci 110(6):627–639. doi:10.1042/cs20050330

    Article  PubMed  CAS  Google Scholar 

  • Yaochite JNU, Caliari-Oliveira C, Davanso MR, Carlos D, Ribeiro Malmegrim KC, Ribeiro de Barros Cardoso C, Ramalho LNZ, Palma PVB, Santana da Silva J, Cunha FQ, Covas DT, Voltarelli JC (2012) Dynamic changes of the Th17/Tc17 and regulatory T cell populations interfere in the experimental autoimmune diabetes pathogenesis. Immunobiol

  • Ye X, Chopp M, Liu X, Zacharek A, Cui X, Yan T, Roberts C, Chen J (2011) Niaspan reduces high-mobility group box 1/receptor for advanced glycation endproducts after stroke in type-1 diabetic rats. Neuroscience 190:339–345. doi:10.1016/j.neuroscience.2011.06.004

    Article  PubMed  CAS  Google Scholar 

  • Yu J, Zeng J, Cheung RT, Xiong L, He M, Liang Z, Hong H, Huang R (2009) Intracerebroventricular injection of epidermal growth factor reduces neurological deficit and infarct volume and enhances nestin expression following focal cerebral infarction in adult hypertensive rats. Clin Exp Pharmacol Physiol 36(5–6):539–546. doi:10.1111/j.1440-1681.2008.05105.x

    Article  PubMed  CAS  Google Scholar 

  • Zaremba J, Skrobanski P, Losy J (2001) Tumour necrosis factor-alpha is increased in the cerebrospinal fluid and serum of ischaemic stroke patients and correlates with the volume of evolving brain infarct. Biomed pharmacother 55(5):258–263

    Article  PubMed  CAS  Google Scholar 

  • Zeller JA, Lenz A, Eschenfelder CC, Zunker P, Deuschl G (2005) Platelet-leukocyte interaction and platelet activation in acute stroke with and without preceding infection. Arterioscler Thromb Vasc Biol 25(7):1519–1523. doi:10.1161/01.ATV.0000167524.69092.16

    Article  PubMed  CAS  Google Scholar 

  • Zhai Y, Busuttil RW, Kupiec-Weglinski JW (2011) Liver ischemia and reperfusion injury: new insights into mechanisms of innate-adaptive immune-mediated tissue inflammation. Am j transplant: off j Am Soc Transplant Am Soc Transplant Surg 11(8):1563–1569. doi:10.1111/j.1600-6143.2011.03579.x

    CAS  Google Scholar 

  • Zhang L, Nair A, Krady K, Corpe C, Bonneau RH, Simpson IA, Vannucci SJ (2004) Estrogen stimulates microglia and brain recovery from hypoxia-ischemia in normoglycemic but not diabetic female mice. J Clin Invest 113(1):85–95

    PubMed  CAS  Google Scholar 

  • Zhao BQ, Tejima E, Lo EH (2007) Neurovascular proteases in brain injury, hemorrhage and remodeling after stroke. Stroke j cereb circ 38(2 Suppl):748–752

    Article  CAS  Google Scholar 

  • Zhou M, Offer A, Yang G, Smith M, Hui G, Whitlock G, Collins R, Huang Z, Peto R, Chen Z (2008) Body mass index, blood pressure, and mortality from stroke: a nationally representative prospective study of 212,000 Chinese men. Stroke j cereb circ 39(3):753–759

    Article  Google Scholar 

  • Zhou X, Nicoletti A, Elhage R, Hansson GK (2000) Transfer of CD4+ T cells aggravates atherosclerosis in immunodeficient apolipoprotein E knockout mice. Circulation 102(24):2919–2922. doi:10.1161/01.cir.102.24.2919

    Article  PubMed  CAS  Google Scholar 

Download references

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Stroke and Vascular Research Centre, Institute of Cardiovascular Sciences, University of Manchester, Manchester Academic Health Science Centre, Salford Royal Foundation Trust, Salford, M6 8HD, UK

    Craig J. Smith

  2. Faculty of Life Sciences, A.V. Hill Building, University of Manchester, Oxford Road, Manchester, M13 9PT, UK

    Catherine B. Lawrence, Beatriz Rodriguez-Grande, Jesus M. Pradillo & Adam Denes

  3. Laboratory of Molecular Neuroendocrinology, Institute of Experimental Medicine, Budapest, 1450, Hungary

    Krisztina J. Kovacs & Adam Denes

Authors
  1. Craig J. Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Catherine B. Lawrence
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Beatriz Rodriguez-Grande
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Krisztina J. Kovacs
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jesus M. Pradillo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Adam Denes
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Craig J. Smith, Catherine B. Lawrence or Adam Denes.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Smith, C.J., Lawrence, C.B., Rodriguez-Grande, B. et al. The Immune System in Stroke: Clinical Challenges and Their Translation to Experimental Research. J Neuroimmune Pharmacol 8, 867–887 (2013). https://doi.org/10.1007/s11481-013-9469-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11481-013-9469-1

Keywords

Search

Navigation