NLRP3 inflammasome activation results in liver inflammation and fibrosis in mice infected with Schistosoma japonicum in a Syk-dependent manner

Ya-Qi Lu,Nan Meng,Shan Zhong,Yin-Ping Fan,Wang-Xian Tang

doi:10.1038/s41598-017-08689-1

Abstract

Granulomatous and fibrosing inflammation in response to soluble egg antigen (SEA) from Schistosoma japonicum (S. japonicum) is the main pathological process of S. japonicum infection. Inflammasome activation has recently been implicated in the pathogenesis of liver disease. However, the role of inflammasome activation in schistosomiasis-associated liver fibrosis (SSLF) has not been extensively studied. In this study, it is demonstrated that the NLRP3 inflammasome is markedly activated in mouse HSCs both in vivo and in vitro during S. japonicum infection. Furthermore, it is demonstrated that inhibition of NLRP3 inflammasome significantly alleviates the liver inflammation and collagen deposition that are induced by infection with S. japonicum. The mechanism of SEA-induced NLRP3 inflammasome activation is studied in isolated, cultured mouse HSCs and it is shown that SEA-induced NLRP3 inflammasome activation in HSCs is dependent upon the activities of spleen tyrosine kinase (Syk), an enzyme usually associated with a pathogen recognition receptor for fungal pathogens. Moreover, it is demonstrated that Dectin-1 and JNK signaling are also involved in SEA-induced NLRP3 inflammasome activation in HSCs. These data shed new light on the mechanisms of NLRP3 inflammasome activation during an infection with S. japonicum, and further characterize its role in schistosomiasis-associated liver fibrosis (SSLF).

Highlights

Schistosomiasis is a neglected tropical disease caused by parasitic flukes of the genus Schistosoma
It was demonstrated that the increased expression of the proteins collagen I and metalloproteinase inhibitor-1 precursor (TIMP-1) after infection with S. japonicum was significantly attenuated in mice infected with AAV8-shNLRP3 (Fig. 2d,e and Supplementary Fig. S2)
In addition to reactive oxygen species (ROS) production and lysosomal activity as potential molecular mechanisms by which the NLRP3 inflammasome is activated, we further identified an upstream protein signaling pathway, spleen tyrosine kinase (Syk), that appeared to be involved in the regulation of soluble egg antigen (SEA)-induced NLRP3 inflammasome activation in vitro

Summary

Introduction

Schistosomiasis is a neglected tropical disease caused by parasitic flukes of the genus Schistosoma. The present authors have recently demonstrated that the activation of caspase-1 could be dependent on the NLRP3 inflammasome during S. japonicum infection. Previous studies by the present authors have found that in vitro activation of NLRP3 inflammasome in cultured mouse hepatic stellate cells (HSCs) is dependent on ROS production and lysosomal activity during S. japonicum infection. The mechanisms of NLRP3 inflammasome activation in HSCs during S. japonicum infection were shown to be dependent on ROS production and lysosomal activity[11]. We aimed to further investigate the role of NLRP3 inflammasome activation in liver fibrogenesis during S. japonicum infection, and to determine whether NLRP3 inflammasome activation in HSCs is dependent on Syk kinase signaling

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