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Title: TRPM2 exacerbates central nervous system inflammation in experimental autoimmune encephalomyelitis by increasing production of CXCL2 chemokines
Authors: Tsutsui, Masato
Hirase, Ryo
Miyamura, Sakie
Nagayasu, Kazuki
Nakagawa, Takayuki
Mori, Yasuo
Shirakawa, Hisashi
Kaneko, Shuji
Author's alias: 筒井, 真人
平瀬, 僚
宮村, 咲映
永安, 一樹
中川, 貴之
森, 泰生
白川, 久志
金子, 周司
Keywords: Experimental autoimmune
encephalomyelitis
TRPM2
Macrophage
Neutrophil
CXCL2
Cytokines
Issue Date: 26-Sep-2018
Publisher: Society for Neuroscience
Journal title: The Journal of Neuroscience
Volume: 38
Issue: 39
Start page: 8484
End page: 8495
Abstract: 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. Evidence suggests that MS is associated with CNS inflammation, although the underlying molecular mechanism is poorly understood. 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 experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Knockout 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, CXCL2 production in TRPM2-KO mice was significantly reduced at Day 14 although the severity of EAE was the same as that in WT mice at that time point. In addition, 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. SIGNIFICANCE STATEMENT: Current therapies for multiple sclerosis (MS), which mainly target lymphocytes, carry the risk of severe side effects and lack efficacy against the progressive form of the disease. Here, we found that the transient receptor potential melastatin 2 (TRPM2) channel, abundantly expressed in CNS-infiltrating macrophages, plays a crucial role in development of experimental autoimmune encephalomyelitis (EAE), an animal model of MS. EAE progression was suppressed by knockout or pharmacological inhibition of TRPM2; this was attributed to a reduction in CXCL2 chemokine production by CNS-infiltrating macrophages in TRPM2-knockout mice, resulting in suppression of neutrophil infiltration into the CNS. These results reveal an important role of TRPM2 in the pathogenesis of EAE and shed light on its potential as a therapeutic target.
Description: 多発性硬化症の新たな病態増悪機構を解明 --TRPM2を介したケモカイン産生が神経炎症の増悪に至る好中球の浸潤を引き起こす--. 京都大学プレスリリース. 2018-09-13.
Rights: © 2018 Authors. This paper was deposited under 'AUTHOR LICENSE POLICY'. (http://www.jneurosci.org/content/rights-permissions)
URI: http://hdl.handle.net/2433/241620
DOI(Published Version): 10.1523/JNEUROSCI.2203-17.2018
PubMed ID: 30201769
Related Link: http://www.kyoto-u.ac.jp/ja/research/research_results/2018/180911_1.html
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