Cell Communication and Signaling (Apr 2024)

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

  • 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

DOI
https://doi.org/10.1186/s12964-024-01601-1
Journal volume & issue
Vol. 22, no. 1
pp. 1 – 24

Abstract

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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.

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