Metformin may reverse some of the autoimmune landmarks in patients with myasthenia gravis (MG), according to an experimental study.
In the rodent study, the spleen showed the highest levels of miR-146a, a microRNA previously linked with autoimmune disorders. On the other hand, lymph nodes and the thymus had decreased levels of the same molecule.
Moreover, T cell subtypes such as Th17 and regulatory T (Treg) cells expressed miR-146a in a lower proportion than B cells. This discrepancy may suggest a target to treat MG.
“Metformin partially inhibited the pathogenicity of AChR-specific B and Th17 cells by targeting miR-146a, and we also predicted the possible downstream target genes of miR-146a in B or T cells,” the authors wrote.
The results were recently published in Immunology Letters.
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The researchers used rat models with experimental autoimmune MG to analyze the expression of microRNAs, their signaling pathways, and their effects on leukocytes.
Metformin has previously demonstrated beneficial effects on patients with this disease, specifically by blocking the Th17 polarization without interfering with induced Treg cells.
In vitro experiments revealed 0.5 mmol/L of metformin interfered with miR-146a expression, and 1 mmol/L successfully upregulated this microRNA in Th17 cells while downregulating it in Treg cells without altering Foxp3 expression. Interestingly, secretion of interleukin-17 also decreased after the second dose of metformin.
Regarding the effects of metformin in B lymphocytes, a single dose of 0.5 mmol/L effectively diminished the expression of miR-146a in experimental autoimmune MG-specific B cells.
Finally, due to these revealing findings, the authors further performed bioinformatics and quantitative polymerase chain reaction trials to identify potential gene targets of miR-154a. A total of 6 genes could be responsible for the effects in both T and B cells, including Brd4, Dot11, Irak1, Siah2, and Traf6. Btg2, Hnrnpd, Kdm2b, Nova1, and Pp1r11 may only relate to T cells and Usp3 to B cells.
“Therefore, miR-146a may serve as a biological marker or a potential therapeutic target of human MG,” the study authors concluded.
Hao Y, Zhao W, Chang L, et al. Metformin inhibits the pathogenic functions of AChR-specific B and Th17 cells by targeting miR-146a. Immunol Lett. Published online September 13, 2022. doi:10.1016/j.imlet.2022.09.002