Administration of a microRNA-21 inhibitor improves the lupus-like phenotype in MRL/lpr mice by repressing Tfh cell-mediated autoimmune responses

• DOI: 10.1016/j.intimp.2022.108578
• Publication Date: 2022-02-03T11:35:47Z
• Authors: Xiaofei Gao; Yang Song; Pei Du; Shuang Yang; Haobo Cui; Shuang Lu; Longyuan Hu; Limin Liu; Sujie Jia; Ming Zhao
• Keywords: Disease Models, Animal; Mice; Mice, Inbred MRL lpr; MicroRNAs; 0303 health sciences; 03 medical and health sciences; Phenotype; T Follicular Helper Cells; Animals; Antagomirs; Lupus Erythematosus, Systemic; 3. Good health

Inhibiting Tfh cell overexpansion prevents autoimmune responses and disease flares in systemic lupus erythematosus (SLE). miR-21 is highly expressed in SLE CD4+ T cells, but whether inhibiting miR-21 can reduce Tfh cell expansion and alleviate the disease progression of lupus is unclear.To address the role and molecular mechanism of miR-21 in regulating Tfh cell expansion and its therapeutic effect on SLE.We treated 12-week-old MRL/lpr mice with Antagomir-21, which specifically inhibited miR-21 in vivo. After 12 weeks of treatment, we examined the proportions of Tfh cells and germinal center (GC) B cells and serum levels of autoantibodies and evaluated disease severity by histological scoring and albuminuria. We determined the level of intracellular free iron in CD4+ T cells by PGSK probe and examined the expression of the Fth and Tfrc genes by qPCR. Immunohistochemistry (IHC)was used to assess the 5-hmC level in the draining lymph nodes (dLNs) and spleen.Inhibiting miR-21 significantly reduced the expansion of Tfh cells and GC B cells. Furthermore, Antagomir-21 highly improved skin lesions and nephritis in MRL/lpr mice. Inhibiting miR-21 reduced intracellular iron accumulation and DNA hydroxymethylation in T cells. In conclusion, inhibiting miR-21 in vivo improves intracellular iron homeostasis and inhibits Tfh cell overexpansion, contributing to reduced autoimmune responses and the remission of disease symptoms in murine lupus.