Exacerbation of intestinal IL-17 activity by mycoplasma superantigen leads to increased HMGB1 and chemokines in the joints of autoimmune arthritis mice

Abstract

Abstract An infection can amplify an autoimmune disease by either exacerbating an ongoing disorder, including a relapse, or by leading to chronic progressive disease. We have been studying a mouse autoimmune arthritis model by infecting mice with the Mycoplasma arthriditis. M. arthritidis produces a potent superantigen (SAg) MAM, which is known to be responsible for the autoimmune arthritis induced in susceptible mouse strains. Because the mechanisms leading from systemic autoimmunity to joint-specific autoimmune disease are still unclear, we questioned if autoimmunity initiates at mucosal sites, i.e., gut and lung. In the present study, mice were systemically immunized with collagen II and MAM superantigen, a week later, IL-17 and HMGB1 (the high mobility group box 1, a stress protein) were highly represented within intestinal lamina propria. Levels of IL-17 and HMGB1 in the gut were closely related to the severity of arthritis. The infiltration of inflammatory leukocytes in the joints were found 3 to 5 weeks after IL-17/HMGB1 were seen in the gut. We also showed that IL-17/HMGB1 synergetically stimulate synoviocytes to release a spectrum of chemokines, CXCL1, CXCL2, CXCL12, CCL2 and CCL5, and attracted inflammatory leukocytes. In vivo blocking of IL-17 and/or HMGB1 greatly reduced arthritis severity and joint destruction. Our results suggests that, the synergetic effect of IL-17 and HMGB1 which initiate autoimmunity in the gut is critical for bridging the inflammatory signals between the gut and the joints, and promoting the infiltration of inflammatory cells in the joints. Thus we might develop a therapeutic strategy to reduce inflammatory response and joint destruction by targeting IL-17 and HMGB1 at mucosal sites in autoimmune arthritis.