PLXDC2 activation by PX-69 ameliorates rheumatoid arthritis through activation of novel immunometabolic mechanisms

Abstract

Abstract Rheumatoid arthritis is a chronic inflammatory disorder that affects up to 1% of the population worldwide characterized by the increased presence of infiltrating immune cells, activation of inflammatory cytokine cascades, oxidative stress, abnormal proliferation of fibroblast-like synoviocytes (FLS) and neovascularization at the joint synovium. Plexin domain containing 2 (PLXDC2) is a transmembrane receptor with antioxidant, antiangiogenic and immunomodulatory properties that provide therapeutic activity in animal models of autoimmune disease, including rheumatoid arthritis. PLXDC2 activation suppresses glycolytic metabolism, while decreasing cytokine and chemokine secretion and production of superoxide species, in immune cells and FLS. In a rat model of collagen-induced arthritis, oral administration of the lead PLXDC2-binding agonist, PX-69, ameliorates disease severity, resulting in decreased clinical scores and paw size. Similarly, hind ankles presented structure preservation, reduced cartilage damage and decreased immune cell infiltration and number of blood vessels in the PX-69-treated group relative to vehicle. Immunologically, PX-69 treatment resulted in a 2-fold decrease of TNFα-producing cells while upregulating the proportion of IL-10+ myeloid cells and regulatory T cells in draining lymph nodes. In synovial tissue, pharmacological activation of PLXDC2 provided greater than 50% reduction in expression of inflammatory mediators (TNFα, IL1β, IL6, Cxcl1) and markers of synoviocyte activation (c-myc, c-fos). These results support the role of PLXDC2 signaling in controlling rheumatoid arthritis and validate PLXDC2 as a novel target for the treatment of this disabling inflammatory disorder.