No abstract

IL-17 is a pro-inflammatory cytokine implicated a variety of autoimmune diseases. We have recently reported that FGF2 cooperates with IL-17 to protect intestinal epithelium during dextran sodium sulfate (DSS)-induced colitis. Here, we report a pathogenic role of the FGF2-IL-17 cooperation in the pathogenesis of autoimmune arthritis. Combined treatment with FGF2 and IL-17 synergistically induced ERK activation as well as the production of cytokines and chemokines in human synovial intimal resident fibroblast-like synoviocytes (FLS). Furthermore, ectopic expression of FGF2 in mouse joints potentiated IL-17-induced inflammatory cytokine and chemokine production in the tissue. In the collagen-induced arthritis (CIA) model, while ectopic expression of FGF2 in vivo exacerbated tissue inflammation and disease symptom in the wild-type controls, the effect was largely blunted in Il17a −/− mice. Taken together, our study suggests that FGF2 cooperates with IL-17 to promote the pathogenesis of autoimmune arthritis by cooperating with IL-17 to induce inflammatory response.

Necroptosis is a recently defined type of programmed cell death with the specific signaling cascade of receptor-interacting protein 1 (RIPK1) and RIPK3 complex to activate the executor MLKL. However, the pathophysiological roles of necroptosis are largely unexplored. Here, we report that fungus triggers myeloid cell necroptosis and this type of cell death contributes to host defense against the pathogen infection. Candida albicans as well as its sensor Dectin-1 activation strongly induced necroptosis in myeloid cells through the RIPK1-RIPK3-MLKL cascade. CARD9, a key adaptor in Dectin-1 signaling, was identified to bridge the RIPK1 and RIPK3 complex-mediated necroptosis pathway. RIPK1 and RIPK3 also potentiated Dectin-1-induced MLKL-independent inflammatory response. Both the MLKL-dependent and MLKL-independent pathways were required for host defense against C. albicans infection. Thus, our study demonstrates a new type of host defense system against fungal infection.