ReviewGlucocorticoids in the control of neuroinflammation
Introduction
Glucocorticoids (GCs) are a class of steroid hormones that are commonly used to treat acute and chronic inflammatory disorders (Tuckermann et al., 2005). They exert most of their functions by binding to the glucocorticoid receptor (GR), which controls gene expression and signalling cascades through genomic as well as non-genomic mechanisms. By this means, GCs modulate the survival, differentiation, migration and various effector functions of leukocytes and other cell types and thereby impact both, innate and adaptive immunity. Whilst GCs administered at pharmacological concentrations are considered purely immunosuppressive, fluctuations in the levels of endogenous GCs, e.g. during stress, result in more complex immunomodulatory effects (Elenkov and Chrousos, 1999).
One major application of GCs is the treatment of neuroinflammatory disorders, in particular multiple sclerosis (MS), the most prevalent chronic autoimmune disease of the central nervous system (CNS) in the Western world (Noseworthy et al., 2000). MS is characterized by infiltrating autoreactive T-cells in the CNS that initiate an inflammatory cascade involving leukocytes and humoral components (Sospedra and Martin, 2005). This causes demyelination and axonal loss, which eventually leads to severe functional deficits. While GCs have no positive effect on the long-term prognosis of MS, optic neuritis and other acute relapses are widely treated with high doses of methylprednisolone (Milligan et al., 1987). Still, such a therapy may lead to severe complications or incomplete recovery. Furthermore, it is known that the course of MS is influenced by the level of endogenous GCs (Elenkov and Chrousos, 1999). Women in the third trimester of pregnancy and Cushing syndrome patients often experience remission of the disease. This is explained by a polarization of the immune system towards TH2 dominated responses as a consequence of increased cortisol synthesis. Thus, fluctuations in GC production impact the course of neuroinflammatory diseases such as MS.
Whilst the importance of GCs for the control of neuroinflammation is doubtless, the mechanism at work is still unclear. Presently the pro-apoptotic function of GCs, their ability to impact migration and extravasation through the blood–brain barrier (BBB) and various influences on the effector functions of immune cells are discussed (Reichardt et al., 2006). While clinical studies have made important contributions to solve these questions, new insight has mainly been achieved using experimental autoimmune encephalomyelitis (EAE), a widely recognized animal model for MS that reflects many hallmarks of the human disease (Gold et al., 2006). It will be important in the future to continue along this line to improve our understanding of the mechanism of GCs in the control of neuroinflammation.
Section snippets
Molecular basis of glucocorticoid actions
The GR, a member of the nuclear receptor superfamily, is involved in the control of a plethora of physiological processes ranging from energy homeostasis and cognitive functions to the modulation of the immune system (Mangelsdorf et al., 1995). In the absence of GCs, the GR is sequestered in a multimeric complex in the cytoplasm. Once GCs have entered the cell, the GR is released and translocates into the nucleus (Beato et al., 1995). After binding to DNA, it drives transcription from so-called
Multiple sclerosis and its animal model experimental autoimmune encephalomyelitis
MS was first described in 1868 by the French neurologist Jean Martin Charcot who observed an accumulation of inflammatory cells in the CNS of patients suffering from periodic episodes of neurological dysfunction (Hafler, 2004). In 1933, Thomas Rivers showed that symptoms similar to the ones seen in MS patients could be induced by repeated injection of rabbit brain homogenate into primates without a need of infectious agents (Rivers et al., 1933). This marks the beginning of the long history of
Induction of apoptosis by glucocorticoids
The phenomenon of GC-induced T cell apoptosis has been recognized almost 30 years ago but the exact mechanism is not yet fully understood (Screpanti et al., 1989). The presence of the GR, DNA-binding dependent transcription and de novo gene expression is required but none of the identified target genes such as the pro-apoptotic proteins Bim and PUMA has turned out to be essential (Erlacher et al., 2005, Reichardt et al., 1998, Wang et al., 2006). Signal transduction events initiated in T cells
Side effects of glucocorticoid therapy
Despite the unsurpassed efficacy of GCs in the treatment of MS, such therapies are accompanied by multiple side effects. These comprise mood disorders, gastrointestinal pain and headache, while chronic administration may additionally lead to osteoporosis, diabetes and an increased susceptibility to infectious diseases (Pozzilli et al., 2004). Importantly, these side effects depend on the duration, dose and combination with other therapeutic agents and complicate MS therapy to a not yet fully
Conclusions and future directions
Despite the long history of GC research and the wide usage of these drugs in the clinical management of MS there are still many open questions. Firstly, which molecular mechanisms underlie the effects of GCs in MS and how could this knowledge be exploited to develop new drugs with an improved therapeutic profile? Also the cellular basis of GC effects continues to attract attention, e.g. which cell-types are the predominant targets of GCs in MS therapy and which of these effects are most
Acknowledgements
This work was supported by grants form the DFG (RE1631/1-3) and the Gemeinnützige Hertie-Stiftung (1.01.1/06/010).
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