Paper

MiR-574-5p activates human TLR8 to promote autoimmune signaling and lupus

Bi, Shulin, Hu, Tao, Yang, Dianqiang, Zheng, Feng, Luo, Yu, Dai, Shuang, Wang, Tao, Shao, Zhiqiang, Cai, Jianchun, Ballestar, Esteban, Song, Dan, Li, Xuejuan, Yang, James Y., Zhang, Yunyun, Liu, Xiaoyan, Zhang, Yan, Chen, Dahan, Kong, Xiaodan, Xing, Yida, Hou, Jinpao

2023

Overview

Endosomal single-stranded RNA-sensing Toll-like receptor-7/8 (TLR7/8) plays a pivotal role in inflammation and immune responses and autoimmune diseases. However, the mechanisms underlying the initiation of the TLR7/8-mediated autoimmune signaling remain to be fully elucidated. Here, we demonstrate that miR-574-5p is aberrantly upregulated in tissues of lupus prone mice and in the plasma of lupus patients, with its expression levels correlating with the disease activity. miR-574-5p binds to and activates human hTLR8 or its murine ortholog mTlr7 to elicit a series of MyD88-dependent immune and inflammatory responses. These responses include the overproduction of cytokines and interferons, the activation of STAT1 signaling and B lymphocytes, and the production of autoantigens. In a transgenic mouse model, the induction of miR-574-5p overexpression is associated with increased secretion of antinuclear and anti-dsDNA antibodies, increased IgG and C3 deposit in the kidney, elevated expression of inflammatory genes in the spleen. In lupus-prone mice, lentivirus-mediated silencing of miR-574-5p significantly ameliorates major symptoms associated with lupus and lupus nephritis. Collectively, these results suggest that the miR-574-5p-hTLR8/mTlr7 signaling is an important axis of immune and inflammatory responses, contributing significantly to the development of lupus and lupus nephritis.

• Publisher: Cold Spring Harbor Laboratory
• Subject: Immunology