Autophagy in Microglia-mediated De- and Re-myelination
Immunology
Final Report Abstract
Microglia, the resident immune cells of the central nervous system (CNS), play an important role not only in CNS homeostasis and repair, but can also contribute significantly to neurological diseases. For example, activation of microglial cells, a process characterized by morphological change and an increase in pro-inflammatory signaling pathways with a concurrent downregulation of homeostatic signaling, is a hallmark of almost all degenerative and chronic immune-mediated neurological diseases. In the demyelinating autoimmune disease Multiple Sclerosis (MS), where the protective myelin-sheath around nerve cells is progressively lost, microglia can have similarly opposing roles. On one hand, microglia promote re-myelination and tissue repair by effectively removing cell debris through degradation and phagocytosis, which in turn allows oligodendrocytes to re-myelinate neurons with damaged or lost sheaths. However, re-myelination fails in the majority of patients, resulting in progressive accumulation of disease. Experiments in mice have shown that insufficient phagocytosis of cell debris after demyelination prevented remyelination and repair of incurred damage. Furthermore, it was shown that a persistent proinflammatory phenotype in microglia was associated with impaired re-myelination. Together this points to the importance of pathways governing not only phagocytic activity but also activation status of microglia. However, these pathways, especially in an immune-mediated CNS disease such as MS, are incompletely understood and poorly characterized. This project was based on the hypothesis that the degradative pathway of autophagy, which had been identified to also mediate a variety of immune functions, might be involved in microglia function in an autoimmune setting. While Conventional Autophagy (CA) is characterized by the enclosure of unnecessary of dysfunctional cell components in a doublemembrane autophagosome, which then turns into an autolysosome for degradation of said components, the associated autophagy-machinery can also be used for a process termed LC3-associated phagocytosis (LAP), which has not only been implicated in clearance of cell debris but also in altering immune activation and inflammatory responses of various cells. However, the role of autophagy-proteins in microglia during CNS homeostasis or upon demyelinating disease are unclear. This project aimed to fill this knowledge gap to potentially identify novel therapeutic targets for people with MS.
Publications
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ATG5 in microglia does not contribute vitally to autoimmune neuroinflammation in mice. Autophagy, 17(11), 3566-3576.
Srimat, Kandadai Keertana; Kotur, Monika B.; Dokalis, Nikolaos; Amrein, Irmgard; Keller, Christian W.; Münz, Christian; Wolfer, David; Prinz, Marco & Lünemann, Jan D.
