Search

Abstract Besides metabolic homeostasis regulation, adipokines are recently emerged as important players in regulating immunity and inflammation. Helminth infection has known to modulate circulating adipokine secretion; however, the regulation and function of adipokines in response to helminth infection is still unclear. Here, we investigated the regulation and function of adiponectin during T. spiralis infection. While there was no change in circulating level of adiponectin, we found an increased adiponectin, but not leptin expression in the small intestine. Interestingly, the intestinal adiponectin expression was strongly associated with the expression of epithelial cell-derived cytokines IL-25, IL-33, and TSLP following infection. Indeed, mice deficiency of IL-25 receptor exhibited no intestinal adiponectin induction upon helminth infection. Interestingly, IL-25-induced adiponectin modulated intestinal epithelial cell responses by enhancing occludin and CCL17 expression. Using LPS-induced intestinal epithelial barrier dysfunctions in a Caco-2 cell monolayer model, adiponectin pretreatment enhanced a Transepithelial electrical resistance (TEER) and occludin expression. More importantly, adiponectin pretreatment of Caco2 cells prevented T. spiralis larval invasion in vitro and its administration during infection enhanced intestinal IL-13 secretion and worm expulsion in vivo. Altogether, our data suggest that intestinal adiponectin expression induced by helminth infection through the regulation of IL-25 promotes worm clearance and intestinal barrier function.

Abstract The epithelial cell-derived cytokines IL-33 and IL-25 are important mediators in driving type-2 inflammation during C. neoformans infection. Nevertheless, the impact of these cytokines in regulating host T helper cell response during C. neoformans infection is still unclear. We observed that C. neoformans infection promoted a predominant increase of T helper cells that co-expressed IL-25 and IL-33 receptors within the lung during the late infection phase. A comparative transcriptomic analysis of effector T helper cells co-treated with IL-25 and IL-33 revealed a cooperative effect of these cytokines in promoting IL-13 gene expression. Without IL-25 receptor signaling, IL-33 treatment upregulated Th1-associated genes and genes associated with nucleotide metabolism. By contrast, IL-25 had a unique effect in enhancing type-2 cytokines IL-5 and IL-9 and chemokine CCL24, as well as genes in the pathways that are associated with L-arginine metabolisms. Interestingly, this pathogenic T helper cell population that expressed IL-25 and IL-33 receptors was greatly enriched in mice that were infected with high cryptococcal virulence and associated with fungal burdens in the brain. Therefore, our data further provide the additional function of IL-25 and IL-33 in potentiating cryptococcal brain dissemination.