IL-22 synergizes with IL-17 to promote mucosal inflammation and bone loss

Abstract

Abstract Interleukin (IL)-22 mediates immune cell communication with nonhematopoietic cells and was shown to exert protective or destructive effects in different disease contexts. In the oral mucosal disease periodontitis, IL-22 has been associated with increased tissue destruction, although cause-and-effect evidence and the underlying mechanisms are lacking. Here, we showed that endogenous IL-22 was required for experimental periodontitis in mice, whereas local administration of exogenous IL-22 exacerbated periodontal inflammation and bone loss. Importantly, the ability of IL-22 to induce expression of inflammatory cytokines and tissue-degrading metalloproteinases as well as cause bone loss required intact IL-17 function, suggesting a potential cooperation between the two cytokines. As human fibroblasts prominently coexpress IL-22 and IL-17 receptors in the periodontal tissue and play a role in the pathogenesis of periodontitis, we examined them in vitro as potential targets of a destructive IL-22–IL-17 interplay. IL-22 synergized with IL-17 for enhanced nuclear factor κB–mediated inflammatory responses (IL-6, matrix metalloproteinase-1) in a STAT3-dependent manner. Analysis of cytosolic and nuclear extracts revealed that IL-22 enhanced nuclear factor κB p65 phosphorylation and translocation to the nucleus of IL-17–stimulated fibroblasts. In conclusion, our study provides causal evidence for IL-22 involvement in periodontitis and describes a hitherto unknown IL-22–IL-17 synergy in inflammatory bone loss.