IL‐17 neutralization significantly ameliorates hepatic granulomatous inflammation and liver damage in Schistosoma japonicum infected mice

Abstract

IL-17 is a signature cytokine of Th17 cells implicated in the induction and progression of chronic inflammatory diseases. Several studies in C57BL/6 mice, immunized with soluble schistosome egg Ags (SEA) in complete Freund's adjuvant (CFA), and subsequently infected with Schistosoma mansoni (S. mansoni) have shown that severe hepatic granulomatous inflammation is correlated with high levels of IL-17. Here, using a Schistosoma japonicum (S. japonicum) larvae infection model in C57BL/6 mice, we analyzed the dynamic expression of IL-17 in infected livers by RT-qPCR and ELISA. Our results showed that IL-17 expression was elevated during the course of infection. The temporal expression of IL-17 and cytokines/chemokines involved in the induction and effector function of Th17 cells was paralleled with hepatic granulomatous inflammation. Treatment of S. japonicum infected mice with IL-17-neutralizing mAb resulted in significant downmodulation of granulomatous inflammation and hepatocyte necrosis. The protection was associated with lower expression of proinflammatory cytokines/chemokines, such as IL-6, IL-1β, CXCL1, and CXCL2 and a reduced number of infiltrating neutrophils. Anti-IL-17 mAb significantly ameliorated hepatic granulomatous inflammation, partly through the downregulation of proinflammatory cytokines/chemokines and recruitment of neutrophils. Our data indicate a pathogenic role of Th17/IL-17 in hepatic immunopathology in S. japonicum infected mice. Keywords: CD4+ T cells r Granulomatous inflammation r IL-17 r Schistosoma japonicum IntroductionSchistosomiasis is a serious global helminth-induced disease, which affects more than 200 million people worldwide [1]. ThereCorrespondence: Jijia Shen e-mail: shenjijia@hotmail.com are three major species that infect humans: Schistosoma japonicum (S. japonicum), Schistosoma mansoni, and Schistosoma haematobium. The common pathological changes, including those in schistosomiasis japonica [2], are granulomatous and fibrotic inflammation against parasite eggs deposited in the liver and intestines. Schistosoma japonicum is mainly distributed in Southeast Asia, is a major public health concern in China. About one million people, more than 1.7 million cattle and other mammals are currently Eur. J. Immunol. 2012Immunol. . 42: 1523Immunol. -1535 infected [3]. It has long been recognized that granuloma formation is a CD4 + T-cell-dependent, cell-mediated process. After infection, immune responses to schistosoma antigens demonstrate a marked switch from a moderate proinflammatory Th1 response to a vigorous Th2-dominated response with the beginning of oviposition around 4 weeks postinfection (p.i.) [4]. Multiple studies on the pathogenesis of granuloma formation have investigated the cytokine patterns mediated by antigen-specific T cells in mice with schistosomiasis japonica. In particular, the roles of the so-called Th1 and Th2 cytokines have been elucidated. The requirement for CD4 + T cells in granulomatous inflammation was verified in MHC class II-deficient mice, which demon...

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