IL-7 suppresses macrophage autophagy and promotes liver pathology in Schistosoma japonicum-infected mice.

Jifeng Zhu,Feng Liu,Weiwei Zhang,Chuan Su,Lei Xu,Zhipeng Xu,Ming Xiao,Lina Zhang,Sha Zhou,Hui Bai,Xiaojun Chen

doi:10.1111/jcmm.13610

Abstract

In schistosomiasis japonica and mansoni, parasite eggs trapped in host liver elicit severe liver granulomatous inflammation that subsequently leads to periportal fibrosis, portal hypertension, haemorrhage or even death. Macrophages are critical for granuloma formation and the development of liver fibrosis during schistosomiasis. However, whether the aberrant regulation of macrophage autophagy has an effect on the development of liver immunopathology in schistosomiasis remains to be elucidated. In this study, we showed that Schistosoma japonicum (S. japonicum) egg antigen (SEA)‐triggered macrophage autophagy limited the development of pathology in host liver. However, engagement of IL‐7 receptor (IL‐7R/CD127) on macrophages by S. japonicum infection‐induced IL‐7 significantly suppressed SEA‐triggered macrophage autophagy, which led to an enhanced liver pathology. In addition, anti‐IL‐7 neutralizing antibody or anti‐CD127 blocking antibody treatment increased macrophage autophagy and suppressed liver pathology. Finally, we demonstrated that IL‐7 protects macrophage against SEA‐induced autophagy through activation of AMP‐activated protein kinase (AMPK). Our study reveals a novel role for IL‐7 in macrophage autophagy and identifies AMPK as a novel downstream mediator of IL‐7‐IL‐7R signalling and suggests that manipulation of macrophage autophagy by targeting IL‐7‐IL‐7R signalling may have the potential to lead to improved treatment options for liver pathogenesis in schistosomiasis.

Highlights

Schistosomiasis is a parasitic disease affecting more than 210 million people worldwide.[1]
In hosts infected with S. japonicum or mansoni, parasite eggs are trapped in hosts’ liver and induce severe liver granulomatous responses, which subsequently lead to liver fibrosis, circulatory impairment or even death.[2,3]
We showed for the first time that IL-7 induced in S. japonicum infection suppressed AMPKdependent macrophage autophagy and enhanced liver immunopathology

Summary

| INTRODUCTION

Schistosomiasis is a parasitic disease affecting more than 210 million people worldwide.[1] Infection of Schistosoma japonicum (S. japonicum) or Schistosoma mansoni (S. mansoni) leads to severe liver granulomatous immunopathology induced by eggs trapped in the liver.[2,3] The granulomatous response is characterized by large influxes of inflammatory cells, macrophages, which compose up to 30% of granuloma cells.[4,5] In addition, as one of the major types of antigenpresenting cells (APC), macrophages play a critical role in the initiation and regulation of granulomatous inflammation by presenting schistosome egg antigens to CD4+ T cells to secrete a variety of cytokines and chemokines.[2,5,6] These factors recruit and activate more macrophages and other inflammatory cells including eosinophils, neutrophils and mononuclear cells to the liver to form granulomas by enveloping the eggs.[5] granuloma macrophages. Our results suggest that induction of macrophage autophagy through IL-7 blockade may be a potential therapeutic strategy against tissue immunopathology in diseases including schistosomiasis

| Ethics statement

| RESULTS

Findings

| DISCUSSION