西斯特
TLR7型
核糖核酸
长非编码RNA
生物
信使核糖核酸
细胞生物学
X-失活
免疫学
受体
基因
遗传学
Toll样受体
X染色体
先天免疫系统
作者
Jonathan D. Crawford,Hong Wang,Daniela Trejo-Zambrano,Raffaello Cimbro,C. Conover Talbot,Mekha A. Thomas,Ashley M. Curran,Alexander Girgis,John T. Schroeder,Andrea Fava,Daniel W. Goldman,Michelle Petri,Antony Rosen,Brendan Antiochos,Erika Darrah
出处
期刊:JCI insight
[American Society for Clinical Investigation]
日期:2023-09-21
卷期号:8 (20)
被引量:6
标识
DOI:10.1172/jci.insight.169344
摘要
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with a dramatic sex bias, affecting 9-times more women than men. Activation of toll-like receptor 7 (TLR7) by self-RNA is a central pathogenic process leading to aberrant production of type-I interferon (IFN) in SLE, but the specific RNA molecules that serve as TLR7 ligands have not been defined. We therefore sought to identify female-specific endogenous RNAs containing canonical TLR7 stimulatory motifs. By leveraging gene expression data and the known sequence specificity of TLR7, we identified the female-specific X-inactive specific transcript (XIST) long non-coding RNA as a uniquely rich source of TLR7 ligands in SLE. XIST RNA stimulated IFNα production by plasmacytoid DCs in a TLR7-dependent manner, and deletion of XIST diminished the ability of whole cellular RNA to activate TLR7. XIST levels were elevated in blood leukocytes from female SLE patients compared to controls, correlated positively with disease activity and the IFN signature, and were enriched in extracellular vesicles released from dying cells in vitro. Importantly, XIST was not IFN-inducible, suggesting that XIST is a driver, rather than a consequence of IFN in SLE. Our work suggests a novel role for XIST RNA as a female-specific danger signal underlying the sex bias in SLE.
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