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PO2-1-13

Macrophage TRPM2 channel plays a critical role in CXCL2-induced neutrophil recruitment and inflammation in the central nervous system of experimental autoimmune encephalomyelitis mouse

[Speaker] Hisashi Shirakawa:1
[Co-author] Masato Tsustui:1, Ryo Hirase:1, Sakie Miyamura:1, Kazuki Nagayasu:1, Shuji Kaneko:1
1:Department of Molecular Pharmacology, Kyoto University, Graduate School of Pharmaceutical Sciences, Japan

Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system (CNS) characterized by demyelination and axonal injury. Current therapies that mainly target lymphocytes do not fully meet clinical need due to the risk of severe side effects and lack of efficacy against progressive MS. Recent studies suggest that MS is associated with CNS inflammation, and activation of monocyte lineage cells, such as microglia and macrophages, in the CNS is characteristic of MS and experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Given that neutrophils that infiltrate the CNS can cause extensive inflammation, demyelination, and axonal damage via production of cytotoxic mediators, inhibition of excessive neutrophil activation and migration into the CNS is important. However, the molecular relationships between activated monocyte lineage cells and infiltrating neutrophils, and the precise mechanisms that regulate EAE progression, remain unresolved. Moreover, there are no potential drug targets that suppress CNS inflammation during EAE progression. Transient receptor potential melastatin 2 (TRPM2), a Ca2+-permeable nonselective cation channel, is expressed at high levels in the brain and by immune cells, including monocyte lineage cells. Here, we show that TRPM2 plays a pathological role in EAE. Knockout or or pharmacological inhibition of TRPM2 inhibited progression of EAE, and TRPM2-knockout (TRPM2-KO) mice showed lower activation of Iba1-immunopositive monocyte lineage cells and neutrophil infiltration of the CNS than wild-type (WT) mice. Moreover, we demonstrate that CXCL2 production was significantly reduced in TRPM2-KO mice at day 14 although the EAE severities were not different between WT and TRPM2-KO mice at the time point. Also, we used bone marrow chimeric mice to show that TRPM2 expressed by CNS-infiltrating macrophages contributes to progression of EAE. Since CXCL2 induces migration of neutrophils, these results indicate that reduced expression of CXCL2 in the CNS suppresses neutrophil infiltration and slows progression of EAE in TRPM2-KO mice. Together, the results suggest that TRPM2 plays an important role in progression of EAE pathology and shed light on its putative role as a therapeutic target for MS.
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