Targeting both IL-17 and CXCR2 in the gut leads to the suppression of arthritis and joint inflammation in the autoimmune arthritis mice driven by a mycoplasma superantigen

Abstract

Abstract Individuals with autoimmune susceptible genes infected with environmental microbial agents might amplify an autoimmune condition by either exacerbating an ongoing disorder, including a relapse, or by leading to chronic progressive disease. Previously we have established an autoimmune arthritis model by infecting mice with the Mycoplasma arthriditis. M. arthritidis produces a potent superantigen (SAg) MAM, which was found to be responsible for the arthritis resembling human RA. In the present study we found that MAM can also activate intestinal immune cells in mice. Because the mechanisms leading from systemic autoimmunity to joint-specific autoimmune disease are unknown, we questioned if the autoimmunity initiates at mucosal sites. To address this question, by injecting mice with collagen II (CII), or with CII+MAM. We found that IL-17 and chemokine receptor CXCR2 were highly expressed within the intestinal lamina propria (LP) in CII+MAM mice but not in traditional CIA mice. In CII+MAM mice, overexpression of IL-17 and CXCR2 in the gut was shown to be strongly related to the arthritis severity. Massive infiltration of inflammatory leukocytes and the upregulation of chemokines, CXCL1, CXCL2, CXCL12, CCL2 and CCL5 in the joint tissues were detected and associated with the increased IL-17 and CXCR2 in the intestinal LP following CII+MAM immunization. Suppression of both IL-17 and CXCR2 at same time by blocking antibodies greatly alleviated arthritis. We also found that neither IL-17 nor CXCR2 alone is sufficient to trigger arthritis. Thus the results suggest that the excessive IL-17 and CXCR2 in the gut are related to the exacerbation of arthritis in a manner by which the inflammatory signals can be connected between the gut and the joints.