TLR9型
TLR7型
促炎细胞因子
生物
系统性红斑狼疮
细胞生物学
炎症
免疫学
受体
先天免疫系统
Toll样受体
基因
免疫系统
基因表达
遗传学
疾病
医学
内科学
DNA甲基化
作者
Claire Leibler,Shinu John,Rebecca A. Elsner,Kayla Thomas,Shuchi Smita,Stephen Joachim,Russell C. Levack,Derrick Callahan,Rachael A. Gordon,Sheldon Bastacky,Ryutaro Fukui,Kensuke Miyake,Sébastien Gingras,Kevin M. Nickerson,Mark J. Shlomchik
出处
期刊:Nature Immunology
[Springer Nature]
日期:2022-09-23
卷期号:23 (10): 1457-1469
被引量:19
标识
DOI:10.1038/s41590-022-01310-2
摘要
In lupus, Toll-like receptor 7 (TLR7) and TLR9 mediate loss of tolerance to RNA and DNA, respectively. Yet, TLR7 promotes disease, while TLR9 protects from disease, implying differences in signaling. To dissect this 'TLR paradox', we generated two TLR9 point mutants (lacking either ligand (TLR9K51E) or MyD88 (TLR9P915H) binding) in lupus-prone MRL/lpr mice. Ameliorated disease of Tlr9K51E mice compared to Tlr9-/- controls revealed a TLR9 'scaffold' protective function that is ligand and MyD88 independent. Unexpectedly, Tlr9P915H mice were more protected than both Tlr9K51E and Tlr9WT mice, suggesting that TLR9 also possesses ligand-dependent, but MyD88-independent, regulatory signaling and MyD88-mediated proinflammatory signaling. Triple-mixed bone marrow chimeras showed that TLR9-MyD88-independent regulatory roles were B cell intrinsic and restrained differentiation into pathogenic age-associated B cells and plasmablasts. These studies reveal MyD88-independent regulatory roles of TLR9, shedding light on the biology of endosomal TLRs.
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