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

• Published in: Cell communication and signaling 2024-04, Vol.22 (1), p.220-220, Article 220
• Main Authors: Wang, Tao, Song, Dan, Li, Xuejuan, Luo, Yu, Yang, Dianqiang, Liu, Xiaoyan, Kong, Xiaodan, Xing, Yida, Bi, Shulin, Zhang, Yan, Hu, Tao, Zhang, Yunyun, Dai, Shuang, Shao, Zhiqiang, Chen, Dahan, Hou, Jinpao, Ballestar, Esteban, Cai, Jianchun, Zheng, Feng, Yang, James Y
• Format: Article
• Language: English
• Subjects: Analysis; Animals; Anti-DNA antibodies; Antibodies; Antinuclear antibodies; Autoantigens; Autoimmune diseases; Autoimmunity; Care and treatment; Cytokines; Diagnosis; Genetic aspects; Genetic engineering; hTLR8; Humans; Immune response; Immunoglobulin G; Inflammation; Interferon; Kidney - metabolism; Ligands; Lupus; Lupus nephritis; Lupus Nephritis - genetics; Lymphatic system; Lymphocytes B; Methods; Mice; Mice, Transgenic; MicroRNA; MicroRNAs; MicroRNAs - genetics; miR-574-5p; MyD88 protein; Pathogenesis; Rheumatoid arthritis; Spleen; Stat1 protein; Systemic lupus erythematosus; Testing; TLR7 protein; Toll-like receptor; Toll-Like Receptor 7 - genetics; Toll-Like Receptor 7 - metabolism; Toll-Like Receptor 8 - genetics; Toll-Like Receptor 8 - metabolism; Toll-like receptors; Transgenic mice; Tumor necrosis factor-TNF
• ISSN: 1478-811X; 1478-811X
• DOI: 10.1186/s12964-024-01601-1

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.