Metformin Seen to Target Immune Cells Driving MG in Early Research
Diabetes treatment may 'rescue' specific T- and B-cells through effects on miR-146a
Treatment with the diabetes medication metformin suppresses the growth of immune T- and B-cell subsets that are implicated in the development of myasthenia gravis (MG), according to a study in a rat model of the neuromuscular disease.
Metformin appeared to exert these positive effects by reversing the abnormal levels of a microRNA molecule called miR-146a in specific immune cell subsets.
“Our study identifies a complex role of miR-146a in the … rat model, suggesting that more caution should be paid in targeting miR-146a for the treatment of MG,” the researchers wrote.
The study, “Metformin Inhibits the Pathogenic Functions of AChR-specific B and Th17 Cells by Targeting miR-146a,” was published in Immunology Letters.
Myasthenia gravis research into role of miR-146a, a key microRNA
In MG, the immune system abnormally produces self-reactive antibodies against proteins critical for nerve-muscle communication, with the most common being the acetylcholine receptor (AChR).
These antibodies are produced by immune B-cells, whose activity can be influenced by various subsets of immune T-cells.
Specifically, T-helper 17 (Th17) cells, which promote B-cell activation and inflammation, are overactive in MG, while T-regulatory cells (Tregs), which suppress the activity of other immune cells, are deficient. This imbalance is thought to be a main driver of the abnormal immune responses that mark myasthenia gravis.
MicroRNAs, commonly referred to as miRNAs, are tiny RNA molecules that work to regulate when, where, and how much of a gene’s protein product will be produced. They act by binding to messenger RNA — the intermediate molecule derived from DNA that guides protein production — and in some way inhibiting or destabilizing it to prevent the protein from being made properly or at all.
MiR-146a “has been identified as a vital regulator of immune reactions,” the researchers wrote, participating in immune cell growth, maturation, and death. Its levels are altered in a number of autoimmune diseases, where it may be important for managing the balance between Th17 and Treg cells.
This microRNA has been found at higher than normal levels in the blood of MG patients, but the mechanisms by which it might influence specific immune cell subsets haven’t been established.
A research team in China explored the potential role of miR-146a in MG using a rat model of AChR-associated MG called the experimental autoimmune myasthenia gravis model (EAMG).
miR-146a levels altered in immune tissues like lymph nodes, spleen
They first found that miR-146a levels were significantly altered in the immune tissues of the rat model compared with healthy animals.
Specifically, levels were decreased in the thymus and lymph nodes, but increased in the spleens of rats with MG-like disease. Of note, the thymus and lymph nodes contain a large number of T-cells, whereas the spleen contains mostly B-cells.
No significant differences were observed in non-immune tissues, including those of the brain, heart, lung, muscles, and liver.
“The lower levels of miR-146a in T cell-enriched immune tissues, and its elevated expression in the spleen suggest that differential [production] of miR-146a may occur in T and B cells,” the researchers wrote.
Consistently, in an analysis of T- and B-cells isolated from the EAMG rats, miR-146a levels were significantly lower in T-cells — both Th17 and Treg subsets — but markedly higher in B-cells when compared with healthy rats.
Metformin, a common oral treatment for type 2 diabetes, has been shown to also regulate inflammation. In a previous study, the same research team showed that metformin eased MG symptoms in the EAMG model by inhibiting Th17 cell growth.
Now, the researchers found that metformin’s use significantly increased miR-146 levels in lab-grown Th17 cells from the EAMG rats, while significantly reducing those in Tregs. It also suppressed Th17 maturation, as previously reported, while the proportion of Tregs didn’t change.
Findings indicated that metformin reduced the Th17/Treg ratio and that the “imbalance between Th17 cells and Treg cells was reversed,” the researchers wrote.
Metformin treatment was also associated with a significant drop in the proportion of B-cells and in the levels of miR-146a in those cells.
The findings “indicate an inhibitory effect of metformin on EAMG-specific B cells and Th17 cells,” the researchers wrote, adding that the medication “may rescue the functions of both Th17 cells and B cells by reversing the expression of miR-146a.”
Moreover, by analyzing three databases, the researchers identified 20 genes whose activity was predicted to be affected by miR-146a, many of which were related to T- or B-cell function. Further analyses in lab-grown T- and B-cells from EAMG rats showed that metformin treatment could alter the levels of some of these genes.
“Our predicted downstream target genes provide insight on the regulatory mechanisms by which miR-146a participates in immune responses,” the team wrote.
“miR-146a may serve as a biological marker or a potential therapeutic target of human myasthenia gravis,” the researchers concluded.