Person:

Song, Xinyang

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.

Although maternal antibodies protect newborns from infection, little is known about how protective antibodies are induced without prior pathogen exposure. Here we show that neonatal mice lacking the capacity to produce IgG are protected by maternal natural IgG antibodies to the enteric pathogen enterotoxigenic Escherichia coli (ETEC) when antibodies are delivered either trans-placentally or through milk. By challenging pups fostered on either maternal antibody¬–sufficient or –deficient dams, we found that milk-derived IgG was critical for protection against ETEC-induced disease. Pups utilize the neonatal Fc receptor (FcRn) to transfer IgG from milk into serum, and this IgG provides protection against systemic and mucosal E. coli infection. The maternal commensal microbiota can induce antibodies that recognize antigens expressed by ETEC and other Enterobacteriaceae species. Induction of maternal antibodies against a commensal Pantoea species confers ETEC protection in pups. The surprising role of the microbiota in eliciting protective antibodies to a specific neonatal pathogen represents an important host defense mechanism against neonatal infection.

The metabolic pathways encoded by the human gut microbiome constantly interact with host gene products through numerous bioactive molecules1. Primary bile acids (BAs) are synthesized within hepatocytes and released into the duodenum to facilitate absorption of lipids or fat-soluble vitamins2. Some BAs (~5%) escape into the colon, where gut commensal bacteria convert them into a variety of intestinal BAs2 that are important hormones regulating host cholesterol metabolism and energy balance via several nuclear receptors and/or G protein–coupled receptors3,4. These receptors play pivotal roles in shaping host innate immune responses1,5. However, the impact of this host–microbe biliary network on the adaptive immune system remains poorly characterized. Here we report that both dietary and microbial factors influence the composition of the gut BA pool and modulate an important population of colonic Foxp3+ regulatory T cells (Tregs) expressing the transcriptional factor RORγ. Genetic abolition of BA metabolic pathways in individual gut symbionts significantly decreases this Treg population. Restoration of the intestinal BA pool increases colonic RORγ+ Treg levels and ameliorates host susceptibility to inflammatory colitis via BA nuclear receptors. Thus, a pan-genomic biliary network interaction between hosts and their bacterial symbionts can control host immunologic homeostasis via the resulting metabolites.