Article Text
Abstract
Inflammation plays an important role in Huntington’s disease (HD) pathology and progression. Chronic activation of microglia and the release of inflammatory cytokines are key inflammatory processes in the brain and are found prior to symptom onset in HD. A main pathway that leads to microglial activation is JAK/STAT signaling, which was recently shown to be increased in the putamen of HD patients. Hence, we aim is to study the role of JAK/STAT-mediated microglial activation in HD. To induce activation in the human microglia cell (HMC) line HMC3, cells were treated with lipopolysaccharide (LPS) and interferon (INF)γ. For inhibition of JAK/STAT, AZD1480 was applied. To express mutant huntingtin (mHTT), the cells were transfected with GFP tagged Q25 or Q97 constructs. Microglia were analysed by flow cytometry, immunocytochemistry and qPCR. Activated microglia showed an upregulation of proinflammatory marker HLA-DR in flow cytometry analysis, elevated STAT1 immunostaining, and an increased expression of IL-6 and SOCS-3 gene expression. We found that microglial activation was dependent on JAK/STAT signaling, since upregulation of HLA-DR and increased STAT1 levels were reversed by AZD1480 treatment. Our data suggest, that the expression of mHTT in microglia increased cell death and reduced cell volume in comparison to the control construct, which could be ameliorated by JAK/STAT inhibition. Taken together, these findings indicate that pathological activation of microglia in HD is related to the JAK/STAT pathway. Understanding the role of microglia and the underlying activation processes is essential to opening new avenues for the development of novel therapeutic targets in HD.