Toll-like receptor-2 regulates macrophage polarization induced by excretory-secretory antigens from Schistosoma japonicum eggs and promotes liver pathology in murine schistosomiasis.

Wenci Gong,Lei Sun,Aiping Yu,Yujuan Shen,Fengjuan Huang,Jianping Cao,Yuxin Xu,Xiaofan Zhang,Henry John Mcsorley

doi:10.1371/journal.pntd.0007000

Wenci Gong, Lei Sun + Show 7 more

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https://doi.org/10.1371/journal.pntd.0007000

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Abstract

Schistosomiasis is endemic to many regions of the world and affects approximately 200 million people. Conventional adaptive T cell responses are considered to be the primary contributors to the pathogenesis of Schistosoma japonicum infection, leading to liver granuloma and fibrosis. However, the functional polarization of macrophages and the associated underlying molecular mechanisms during the pathogenesis of schistosomiasis remains unknown. In the present study, we found that excretory-secretory (ES) antigens derived from S. japonicum eggs can activate macrophages, which exhibit an M2b polarization. Furthermore, ES antigen-induced M2b polarization was found to be dependent on enhanced NF-κB signaling mediated by the MyD88/MAPK pathway in a TLR2-dependent manner. In addition, the cytokine profile of the liver macrophages from wild-type-infected mice are quite distinct from those found in TLR2 knockout-infected mice by quantitative PCR analysis. More importantly, the size of granuloma and the severity of the fibrosis in the livers of TLR2-/- mice were significantly reduced compared to that in WT mice. Our findings reveal a novel role for M2b polarization in the pathogenesis of schistosome infection.

Highlights

Schistosomiasis is one of the most important health problems in developing countries[1], and can be used as a chronic disease model for investigating the interplay between the immune response and parasite pathogenicity in the host[2]
We show that activated macrophages play a novel role in the promotion of hepatic granuloma formation and liver fibrosis in a Schistosoma
We identified a novel role for macrophages in liver pathogenesis using a S. japonicum-infected mouse model and present TLR2 signaling as a novel potential therapeutic target for schistosomiasis

Summary

Introduction

Schistosomiasis is one of the most important health problems in developing countries[1], and can be used as a chronic disease model for investigating the interplay between the immune response and parasite pathogenicity in the host[2]. Soluble S. japonicum egg antigens (SjEA) can upregulate programmed death ligand 2 (PD-L2) expression on bone marrowderived dendritic cells (BMDCs) in a TLR2-dependent manner to help inhibit T cell responses in S. japonicum infected mice[2]. These data indicate that interactions between host TLRs and pathogen-associated molecular patterns (PAMPs) from schistosome eggs can initiate a Th2-biased immune response and contribute to the egg-induced immunopathology observed in schistosomiasis

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