Activation of microglia by aggregated beta-amyloid or lipopolysaccharide impairs MHC-II expression and renders them cytotoxic whereas IFN-gamma and IL-4 render them protective.
'Protective autoimmunity' refers to a well-controlled anti-self response that helps the body resist neurodegeneration. The response is mediated by autoimmune T cells, which produce cytokines and growth factors. Using an in vitro assay of hippocampal slices, we show that the cytokines interferon-gamma and (especially) interleukin-4, characteristic of pro-inflammatory and anti-inflammatory T cells, respectively, can make microglia neuroprotective. Aggregated beta-amyloid, like bacterial cell wall-derived lipopolysaccharide, rendered the microglia cytotoxic. Cytotoxicity was correlated with a signal transduction pathway that down-regulates expression of class-II major histocompatibility proteins (MHC-II) through the MHC-II-transactivator and the invariant chain. Protection by interleukin-4 was attributed to down-regulation of tumor necrosis factor-alpha and up-regulation of insulin-like growth factor I. These findings suggest that beneficial or harmful expression of the local immune response in the damaged CNS depends on how microglia interpret the threat, and that a well-regulated T-cell-mediated response enables microglia to alleviate rather than exacerbate stressful situations in the CNS.
Butovsky
Oleg
O
Department of Neurobiology, The Weizmann Institute of Science, 76100 Rehovot, Israel.
Talpalar
Adolfo E
AE
Ben-Yaakov
Keren
K
Schwartz
Michal
M
D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000276:immunology / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D015551:Autoimmunity / Q000187:drug effects / Q000276:immunology; D002460:Cell Line; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D004660:Encephalitis / Q000276:immunology* / Q000503:physiopathology / Q000628:therapy; D005911:Gliosis / Q000276:immunology* / Q000503:physiopathology / Q000628:therapy; D006624:Hippocampus / Q000187:drug effects / Q000276:immunology / Q000503:physiopathology; D000949:Histocompatibility Antigens Class II / Q000187:drug effects / Q000276:immunology*; D007334:Insulin-Like Growth Factor I / Q000187:drug effects / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology* / Q000494:pharmacology; D015847:Interleukin-4 / Q000276:immunology* / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000276:immunology / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D017628:Microglia / Q000187:drug effects / Q000276:immunology*; D019636:Neurodegenerative Diseases / Q000276:immunology / Q000503:physiopathology / Q000628:therapy; D009924:Organ Culture Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000276:immunology
D016229:Amyloid beta-Peptides; D000949:Histocompatibility Antigens Class II; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D007334:Insulin-Like Growth Factor I; D007371:Interferon-gamma