Investigating the NLRP3 inflammasome and its regulator miR-223-3p in multiple sclerosis and experimental demyelination

被引:18
|
作者
Galloway, Dylan A. [1 ]
Carew, Samantha J. [1 ]
Blandford, Stephanie N. [1 ]
Benoit, Rochelle Y. [1 ]
Fudge, Neva J. [1 ]
Berry, Tangyne [1 ]
Moore, George R. Wayne [2 ]
Barron, Jane [3 ]
Moore, Craig S. [1 ,4 ]
机构
[1] Mem Univ Newfoundland, Div Biomed Sci, Fac Med, 300 Prince Philip Dr, St John, NF, Canada
[2] Univ British Columbia, Dept Pathol & Lab Med, Fac Med, Vancouver, BC, Canada
[3] Mem Univ Newfoundland, Discipline Lab Med, Fac Med, St John, NF, Canada
[4] Mem Univ Newfoundland, Discipline Med Neurol, Fac Med, St John, NF, Canada
基金
加拿大健康研究院;
关键词
inflammasome; macrophage; microglia; microRNA; multiple sclerosis; NLRP3; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; INDUCED IL-1-BETA SECRETION; MICROGLIA; ACTIVATION; CASPASE-1; MICRORNAS; CNS; INTERLEUKIN-1-BETA; REMYELINATION; EXPRESSION;
D O I
10.1111/jnc.15650
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Innate immune signaling pathways are essential mediators of inflammation and repair following myelin injury. Inflammasome activation has recently been implicated as a driver of myelin injury in multiple sclerosis (MS) and its animal models, although the regulation and contributions of inflammasome activation in the demyelinated central nervous system (CNS) are not completely understood. Herein, we investigated the NLRP3 (NBD-, LRR- and pyrin domain-containing protein 3) inflammasome and its endogenous regulator microRNA-223-3p within the demyelinated CNS in both MS and an animal model of focal demyelination. We observed that NLRP3 inflammasome components and microRNA-223-3p were upregulated at sites of myelin injury within activated macrophages and microglia. Both microRNA-223-3p and a small-molecule NLRP3 inhibitor, MCC950, suppressed inflammasome activation in macrophages and microglia in vitro; compared with microglia, macrophages were more prone to inflammasome activation in vitro. Finally, systemic delivery of MCC950 to mice following lysolecithin-induced demyelination resulted in a significant reduction in axonal injury within demyelinated lesions. In conclusion, we demonstrate that NLRP3 inflammasome activity by macrophages and microglia is a critical component of the inflammatory microenvironment following demyelination and represents a potential therapeutic target for inflammatory-mediated demyelinating diseases, including MS.
引用
收藏
页码:94 / 112
页数:19
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