Inflammasome-mediated activation of microglia: Tissue-specific features of innate immunity

Abstract

Multiple sclerosis (MS) is a chronic neurodegenerative disease where lesions are found within the brain. Although the exact cause of MS is unknown, these lesions are characterized by activation of immune cells, including microglia and macrophages. Microglia are the resident innate immune cells of the brain. Macrophages are their blood-derived counterparts. Macrophages are normally not present in the brain, but can infiltrate the brain during pathological conditions. What activates microglia and macrophages in MS lesions is unknown yet. In general, microglia and macrophages become activated by detection of molecules derived from pathogens or damaged tissue. Microglia and macrophages express many different receptors that can recognize these molecules, including NOD-like receptors (NLR). NLR are involved in the formation of protein complexes, called inflammasomes, that can lead to the secretion of the cytokine interleukin (IL)-1β. When IL-1β is released by microglia or macrophages it can attract and activate other immune cells, starting an immune cascade. Recent studies show that inflammasome activation plays an important role in the development of some neurodegenerative diseases, such as Alzheimer’s disease. Little was known however about the role of inflammasomes in MS. The aim of this thesis was to investigate whether inflammasome-mediated activation of microglia and macrophages plays a role in the development of MS lesions. We studied IL-1β production in brain tissue of MS patients and compared that to rhesus macaques with EAE, an animal model for MS. We found more IL-1β in EAE lesions than in MS lesions. More importantly we found IL-1β in clusters of activated microglia in otherwise unaffected tissue in MS only, suggesting a very early stage of lesion formation. Furthermore, we observed that microglia, and not the infiltrating macrophages, were the main source of IL-1β. This is particularly remarkable, as both cell types are able to produce IL-1β. Recent studies have shown that differences in origin and environment affect how microglia and macrophages respond. To investigate this in more detail, we used in vitro models for microglia and macrophages derived from healthy, adult rhesus macaques that were euthanized for other scientific research. We describe that microglia and other macrophages express in principal a similar profile of inflammasome proteins and both cell types can form inflammasomes. However, we found important cell type-specific differences, pertaining to differences in the kinetics of inflammasome-mediated response, inflammatory caspase use and the regulation of IL-1β secretion. In general, microglial IL-1β production and secretion can be characterized as reduced, slower and more chronic when compared to other macrophages. In conclusion, we showed that IL-1β might play a role in the early development of MS lesions. Furthermore, we uncovered important differences between microglia and hematopoietic macrophages in the regulation of the inflammasome-mediated response. These results are consistent with tissue-specific innate immune responses in the brain and suggest that microglia and macrophages can be targeted separately by therapeutic interventions. Finally, we discuss how the use of non-human primates may be reduced by the development of alternative methods for studying biomedical research questions.