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

被引:9
作者
Wang, Tao [1 ,11 ]
Song, Dan [1 ]
Li, Xuejuan [2 ,3 ,4 ]
Luo, Yu [6 ]
Yang, Dianqiang [1 ]
Liu, Xiaoyan [4 ]
Kong, Xiaodan [7 ]
Xing, Yida [7 ]
Bi, Shulin [1 ]
Zhang, Yan [1 ]
Hu, Tao [8 ]
Zhang, Yunyun [1 ]
Dai, Shuang [1 ]
Shao, Zhiqiang [1 ]
Chen, Dahan [1 ]
Hou, Jinpao [1 ]
Ballestar, Esteban [2 ,3 ,9 ]
Cai, Jianchun [5 ]
Zheng, Feng [2 ,3 ,4 ,10 ]
Yang, James Y. [1 ,2 ,3 ]
机构
[1] Xiamen Univ, Innovat Ctr Cell Signaling Network, Sch Life Sci, State Key Lab Cellular Stress Biol, Xiamen 361102, Peoples R China
[2] East China Normal Univ, Wuhu Hosp, Wuhu 241000, Peoples R China
[3] East China Normal Univ, Kidney Hlth Inst, Hlth Sci Ctr, Shanghai 200241, Peoples R China
[4] Dalian Med Univ, Hosp 2, Dept Nephrol, Dalian 116144, Peoples R China
[5] Xiamen Univ, Med Coll, Inst Gastrointestinal Oncol, Dept Gastrointestinal Surg,Zhongshan Hosp, Xiamen 361005, Fujian, Peoples R China
[6] Third Mil Med Univ, Sch Nursing, Chongqing 400038, Peoples R China
[7] Dalian Med Univ, Affiliated Hosp 2, Dept Rheumatol, Dalian 116023, Peoples R China
[8] Xiamen Univ, Coll Med, Xiamen 361102, Peoples R China
[9] Josep Carreras Leukaemia Res Inst IJC, Epigenet & Immune Dis Grp, Badalona 08916, Barcelona, Spain
[10] Dalian Med Univ, Adv Inst Mol Med, Dalian 116144, Peoples R China
[11] Xiamen Univ, Affiliated Hosp 1, Sch Med, Key Lab Urinary Tract Tumors & Calculi,Dept Urol, Xiamen 361003, Peoples R China
关键词
Toll-like receptor; miR-574-5p; hTLR8; Autoimmunity; Systemic lupus erythematosus; Lupus nephritis; TOLL-LIKE RECEPTORS; SINGLE-STRANDED RNA; DENDRITIC CELLS; CIRCULATING MICRORNAS; INNATE IMMUNITY; NUCLEIC-ACID; RECOGNITION; EXPRESSION; TOLL-LIKE-RECEPTOR-7; BACTERIAL;
D O I
10.1186/s12964-024-01601-1
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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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页数:24
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