Hypoxia inducible factor 1a perpetuates synovial fibroblast interactions with T cells and B cells in rheumatoid arthritis
Synovial fibroblast hyperplasia, T cell hyperactivity, B cell overactivation, and the self perpetuating interactions among these cell types are major characteristics of rheumatoid arthritis (RA) The inflamed joints of RA patients are hypoxic, with upregulated expression of hypoxia inducible factor 1a (HIF 1a) in RA synovial fibroblasts (RASFs) It remains unknown whether HIF 1a regulates interactions between RASFs and T cells and B cells. We report here that HIF 1a promotes the expression of inflammatory cytokines IL 6, IL 8, TNF a, and IL 1b, and cell cell contact mediators IL 15, vascular cell adhesion molecule (VCAM) 1, thrombospondin (TSP) 1, and stromal cell derived factor (SDF) 1 in RASFs. Furthermore, HIF 1a perpetuates RASF mediated inflammatory Th1 and Th17 cell expansion while differentially inhibiting regulatory B10 and innate like B cells, leading to increased IFN g, IL 17, and IgG production and decreased protective natural IgM secretion. Our findings suggest that HIF 1a perpetuates the interactions between RASFs and T cells and B cells to induce inflammatory cytokine and autoantibody production, thus exacerbating the severity of RA. Targeting HIF 1a may provide new therapeutic strategies for overcoming this persistent disease.
European journal of immunology