Microglia suppress the secondary progression of autoimmune encephalomyelitis

Abstract

Secondary progressive multiple sclerosis (SPMS) is an autoimmune disease of the central nervous system (CNS) characterized by progressive motor dysfunction, sensory deficits, and visual problems. The pathological mechanism of SPMS remains poorly understood. In this study, we investigated the role of microglia, immune cells in the CNS, in a secondary progressive form of experimental autoimmune encephalomyelitis (EAE), the mouse model of SPMS. We induced EAE in nonobese diabetic mice and treated the EAE mice with PLX3397, an antagonist of colony stimulating factor‐1 receptor, during secondary progression in order to deplete microglia. The results showed that PLX3397 treatment significantly exacerbated secondary progression of EAE and increased mortality rates. Additionally, histological analysis showed that PLX3397 treatment significantly promoted inflammation, demyelination, and axonal degeneration. Moreover, the number of CD4+ T cells in the spinal cord of EAE mice was expanded due to PLX3397‐mediated proliferation. These results suggest that microglia suppressed secondary progression of EAE by inhibiting the proliferation of CD4+ T cells in the CNS.

Microglial depletion under thalamic hemorrhage ameliorates mechanical allodynia and suppresses aberrant axonal sprouting

“…Flow cytometry experiments also showed a significant reduction in the number of (CX3CR1 hi ) microglia on postlesion days 7 and 21 in the 4 PLX-treated groups ( Figure 3, C and D) compared with that in the no-PLX treatment TH groups. Based on the previous reports, the effects of PLX treatment on peripheral circulating CSF1Rpositive myeloid cells are known to be limited (25)(26)(27)(28). We also confirmed the number of infiltrating macrophages and neutrophils after PLX treatment (Supplemental Figure 4, A and B).…”

“…Although minocycline is commonly used to halt microglial activity, it has a nonspecific effect on macrophages, T cells, neuronal cells (30)(31)(32)(33), and even on astrocytes (34); all of them are suggested to be involved in the pathogenesis of neuropathic pain (22,(35)(36)(37)(38)(39)(40)(41). In contrast, treatment with a CSF1R inhibitor results in effective ablation of microglia with minor effect on other cells (25)(26)(27)(28), which is also supported by our flow cytometry data, although we cannot fully exclude the possible influence of PLX3397 treatment on peripheral CSF1R-positive circulating myeloid cells. To elucidate the precise mechanism of microglial involvement in the development and maintenance of CPSP, future studies using more specific genetic tools will be needed (22, 42-44).…”

Microglia Diversity in Health and Multiple Sclerosis

“…Microglia prevent the migration of infiltrating macrophages into spared tissue (8), and may also serve important "gate-keeping" functions for other leukocytes that are toxic during EAE. The roles of microglia are likely to evolve throughout the disease, as demonstrated by the finding that microglia ablation with a Csf1 inhibitor during EAE progression accelerates clinical disability (108).…”

Prostaglandin D2 signaling in dendritic cells is critical for the development of EAE

“…6B and K) indicated that DC effects were dominant in PTGDR −/− mice, although effects may also be mediated by monocyte-derived DCs. Monocyte-derived macrophages are also critical for EAE development through expression of pro-inflammatory molecules essential for the development of neuroinflammation [1,[49][50][51]. Microglia have dual roles in EAE, in enhancing and prolonging neuroinflammation [52,53], but also suppressing relapse in relapsing-remitting EAE by inhibiting the proliferation of CD4 T cells in the CNS [54].…”