Regulation and function of adiponectin in the intestinal epithelial cells in response to Trichinella spiralis infection.

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.

IL-25 Receptor Signaling Modulates Host Defense against Cryptococcus neoformans Infection.

Cryptococcal meningitis is one of the most common life-threatening diseases caused by Cryptococcus infection. Increasing evidence indicates that type 2 immunity is associated with disease progression by promoting fungal growth and dissemination. However, factors that govern this pathogenic response during infection are still elusive. In this study, we investigated the role of IL-25, one of the type 2-inducing cytokines produced by epithelial cells, in contributing to the pathogenesis of cryptococcosis. We found that pulmonary but not systemic infection with a high-virulence strain of C. neoformans significantly induced pulmonary IL-25 expression in the lungs but not brains. In response to pulmonary infection, mice deficient in the surface IL-17 receptor B, a component of the IL-25R, exhibited improved survival with a decreased brain fungal burden. The absence of IL-25R signaling diminished the type 2 and enhanced the type 1 immune response that directed macrophage polarization toward M1 macrophages. Interestingly, Cryptococcus-mediated IL-25 signaling suppressed the expression of cytokines and chemokines associated with protection in the brain, including Ifng, Il1b, Ip10, and Nos2, without affecting brain cellular inflammation and microglia cell activation. Il17rb-/- mice receiving cryptococcal-specific CD4+ T cells from wild-type had a shorter survival time with higher fungal burden within the brain and an elevated expression of M2 macrophage markers than those receiving cryptococcal-specific CD4+ T cells from Il17rb-/- mice. Taken together, our data indicated that IL-25 signaling subverts the induction of protective immunity and amplifies the type 2 immune response that may favor the development of cryptococcal disease and the fungal dissemination to the CNS.