Polymer of methyl malonic acid suppress inflammation by downregulating IL-2 through ROS overproduction

Abstract

Metabolites belonging to the propionate metabolism pathway can regulate immune cell responses in the context of autoimmunity and chronic inflammation. Methyl malonic acid (MMA), a metabolite in this pathway is known to cause dysregulation of T cell oxidative phosphorylation (OXPHOS) and downregulating pro inflammatory T cell effector functions. However, the effects of MMA on T cell signaling and T cell activation is not clearly known. Furthermore, since MMA is a small molecule, using it in the context of therapy remains a problem. It gets metabolized in a short time and millimolar concentrations are required to get effective results. This work describes a novel polymer, 1,6 MMA, synthesized using 1,6 Hexane-diol and MMA, which helps in slow, steady and continuous release of the small molecule. Doses in micromolar ranges generate long lasting and robust immunosuppression of activated T cells via an IL2 dependent mechanism in both human and mice T cells without causing non-specific toxicity. This causes a dysregulated expression of pSTAT5 which eventually enhances BLIMP1 mediated T cell apoptosis. Finally, 1,6 MMA mediated T cell suppression is caused due to increase in mitochondrial ROS production. Extrapolation of our findings in-vivo showed the polymer inhibited autoreactive T cell responses in mice with collagen induced arthritis (CIA). Overall, 1,6 MMA, a novel metabolite polymer, has major therapeutic potential in combating inflammatory disorders.