Pim1 Serves as a Therapeutic Target for Inflammatory Arthritis via Mitochondrial Metabolism and Th17 Cell Differentiation.

Inflammatory arthritis, mainly including rheumatoid arthritis (RA) and ankylosing spondylitis (AS), is a group of chronic progressive autoimmune diseases that destroy joints. T helper 17 (Th17) cells are extensively involved in the joint inflammation as well as bone and cartilage destruction of these diseases. Previously, proviral integration site for Moloney-murine leukemia virus 1 (Pim1) was reported to be involved in various autoimmune diseases by mediating the proinflammatory effects of T cells. However, the pathological effect and the therapeutic potential of Pim1 in inflammatory arthritis remain elusive. The present study demonstrated that Pim1 expression was elevated in CD4(+) T cells locally and systemically in patients with RA or AS and in 2 mice models of inflammatory arthritis. Conditional knockdown of Pim1 in CD4(+) T cells (Pim1 cKO) or using the Pim1 inhibitor AZD1208 alleviated the development of inflammatory arthritis in association with decreasing the proportion of Th17 cells. In vitro experiments involving inhibition and overexpression confirmed the promoting effect of Pim1 on Th17 cell differentiation. Mechanistically, Pim1 phosphorylated mitochondrial calcium uptake protein 1 to increase mitochondrial calcium influx, which subsequently activated mitochondrial oxidative phosphorylation and promoted Th17 cell differentiation. Through molecular docking and dynamic simulation, nilotinib, a Food-and-Drug-Administration-approved drug, was identified as a selective substitute for the currently clinically nonapproved Pim1 inhibitors, which impeded Th17 cell differentiation and was well tolerated during the treatment of Pim1 cKO mice and 2 inflammatory arthritis mouse models. Our study contributes to a better understanding of the mechanism through which Pim1 promotes Th17 cell differentiation and advances the clinical application of Pim1 as an effective target for treating inflammatory arthritis.