期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 289, 期 7, 页码 4173-4179出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M113.533034
关键词
Cytokine; Immunology; Innate immunity; Interleukin; Neuroimmunology
资金
- National Multiple Sclerosis Society (NMSS) [CA-10530A-8, RG-1785G9/2]
- Cancer Research Institute
- NMSS
- Canadian Institutes of Health and Research
Background: The nucleotide-binding leucine-rich repeat (NLR) family of innate immune genes are important regulators of inflammatory responses in mammals. Results: The NLR gene, Nlrx1, suppresses neuroinflammation in vivo and inhibits microglial (Mg) activation. Conclusion: NLRX1 immunosuppressive function in Mg correlates with suppression of neuroinflammation during mouse models of Multiple Sclerosis (MS). Significance: NLR genes can have protective roles during neuroinflammation. The nucleotide binding domain and leucine-rich repeat-containing (NLR) family of proteins is known to activate innate immunity, and the inflammasome-associated NLRs are prime examples. In contrast, the concept that NLRs can inhibit innate immunity is still debated, and the impact of such inhibitory NLRs in diseases shaped by adaptive immune responses is entirely unexplored. This study demonstrates that, in contrast to other NLRs that activate immunity, NLRX1 plays a protective role in experimental autoimmune encephalomyelitis (EAE), a mouse model for multiple sclerosis. When compared with wild-type controls, Nlrx1(-/-) mice have significantly worsened clinical scores and heightened CNS tissue damage during EAE. NLRX1 does not alter the production of encephalitogenic T cells in the peripheral lymphatic tissue, but Nlrx1(-/-) mice are more susceptible to adoptively transferred myelin-reactive T cells. Analysis of the macrophage and microglial populations indicates that NLRX1 reduces activation during both active and passive EAE models. This work represents the first case of an NLR that attenuates microglia inflammatory activities and protects against a neurodegenerative disease model caused by autoreactive T cells.
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