miR142 silencing alleviates retinal inflammation by impairing mitochondrial function and reprogramming metabolism of CD4 T cells via targeting MTFR1.

Background: Autoimmune uveitis is a sight-threatening inflammatory disease of the retina. MicroRNA-142 (miR-142) has been implicated in its pathogenesis. This study aimed to elucidate the role of miR-142 in uveitis and its underlying mechanisms.

Methods: The expression of miR-142-3p was analyzed in peripheral blood mononuclear cells from uveitis patients and in experimental autoimmune uveitis (EAU) models. With EAU induction for 14 days, clinical and histopathological scores were graded to evaluate the retinal inflammation. To investigate the effects of miR-142 deficiency on uveitis development, the miR-142 knockout (miR-142) mouse model was used. The miR-142 T cell phenotype and function were characterized using flow cytometry and single-cell sequencing for both in vivo and in vitro experiments. The Seahorse Analyzer, mitochondrial staining and electron microscope analysis were conducted to reveal the mitochondrial function and morphology. And then Luciferase Assays and Western-Blot analysis were used to explore the target of miR-142.

Results: We found that miR-142-3p was significantly up-regulated in uveitis and that its deletion in mice prevented EAU development. The T cell isolated from miR-142 mice lose its uveitogenic nature. T cell lacking miR-142 exhibited reduced numbers and attenuated pathogenicity in uveitis, characterized by decreased proliferation, increased apoptosis, and abnormal differentiation. Single-cell sequencing, energy metabolism analysis and flow cytometry analysis unveiled metabolic reprogramming in miR-142 T cells, with a distinct shift toward glycolysis and restrained oxidative phosphorylation. Further investigation revealed mitochondrial fission regulator 1 (MTFR1) as a direct target of miR-142. The over-expressed protein of MTFR1 in CD4 T cells was found in miR-142 mice.

Conclusions: Our findings highlight the indispensable role of miR-142 in maintaining T cell mitochondrial function. By modulating MTFR1, miR-142 orchestrates mitochondrial homeostasis, metabolic alterations, apoptosis susceptibility, and proliferation capacity in T cells, thereby influencing susceptibility to autoimmune uveitis.