Abstract
The major pathological changes during Schistosoma J. infection are characterized by granulomatous inflammation in the liver, a cellular immune response to schistosomal egg antigens. The molecular mechanisms initiating or promoting this schistosomal granulomatous inflammation remain poorly understood. In the present study, we first demonstrated that in mice infected with Schistosoma J. for 6 weeks exhibited increased levels of IL-1β in liver, a major product of NLRP3 inflammasomes and collagen deposition around the eosinophilic granuloma with Schistosoma J. eggs, which was substantially attenuated by caspase-1 inhibitor, YVAD. This activation of the NLRP3 inflammasome occurred in hepatic stellate cells (HSCs), as shown by a marked increase in co-localization of IL-1β with HSCs marker, desmin. Using isolated, cultured mouse HSCs, we further explored the mechanisms by which soluble egg antigen (SEA) from Schistosoma J. activates NLRP3 inflammasomes. SEA induced the formation and activation of NLRP3 inflammasomes, which was associated with both redox regulation and lysosomal dysfunction, but not with potassium channel activation. These results suggest that NLRP3 inflammasome activation in HSCs may serve as an early mechanism to turn on the inflammatory response and thereby instigate liver fibrosis during Schistosoma J. infection.
Highlights
Epidemiologic studies have indicated that schistosomiasis remains the second most common tropical disease with the high impact on human health due to blood flukes of the genus schistosoma
We demonstrated that Schistosoma J. infection or soluble egg antigens (SEA) from Schistosoma J. eggs induced the formation and activation of NLRP3 inflammasomes in hepatic stellate cells (HSCs) in both in vitro and in vivo
In the mice infected for 6 weeks with Schistosoma J. cercariae, confocal microscopy studies showed increased colocalization of IL-1β with HSCs marker desmin around the Schistosoma J. eggs in the portal area, which can be inhibited by caspase-1 inhibitor YVAD
Summary
Epidemiologic studies have indicated that schistosomiasis remains the second most common tropical disease with the high impact on human health due to blood flukes of the genus schistosoma. Various aetiological factors may lead to chronic liver injuries toward hepatic fibrosis or even cirrhosis such as drug abuses, alcoholism, hepatitis B and C viral infection, Schistosoma J. infection is one of the most common causes for hepatic fibrosis in some countries [5, 6]. It is well known that Schistosoma J. infection is characterized by pronounced immunological and inflammatory reactions against eggs deposited into liver or intestines, which eventually induce liver fibrosis, namely, schistosomiasis-associated liver fibrosis (SSLF) [7]. The precise mechanisms that mediate this perpetual activation of inflammation around egg granulomas in the liver during Schistosoma J. infection remain poorly understood
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