MiR-574-5p Activates Human TLR8 to Promote Autoimmune Signaling and Lupus

Authors

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

Publication Date

4-8-2024

Journal

Cell Communication and Signaling

Abstract

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.

Keywords

Humans, Mice, Animals, Lupus Nephritis, Toll-Like Receptor 7, Toll-Like Receptor 8, Kidney, Mice, Transgenic, MicroRNAs