Corilagin Counteracts IL-13Rα1 Signaling Pathway in Macrophages to Mitigate Schistosome Egg-Induced Hepatic Fibrosis.

Yun-Fei Chen,Yi-Ping Dang,Yao Wang,Quan-Qiang Li,Zhen-Zhong Shang,Lei Luo,Yi-Qing Li,Juan Zhang,Qian Ma,Lei Zhao,Yu-Jie Wang

doi:10.3389/fcimb.2017.00443

Abstract

The IL-13Rα1 signaling pathway and M2 macrophages play crucial roles in schistosome egg-induced hepatic fibrosis via the expression of pro-fibrotic molecules. This study aims to investigate the inhibitory effect and mechanism of action of corilagin on schistosome egg-induced hepatic fibrosis via the IL-13Rα1 signaling pathway in M2 macrophages in vitro and in vivo. The mRNA and protein expression of IL-13Rα1, PPARγ, KLF4, SOCS1, STAT6, p-STAT6, and TGF-β was measured in vitro with corilagin treatment after IL-13 stimulation and in vivo corilagin treatment after effectively killing the adult schistosomes in schistosome-infected mice. Histological analysis of liver tissue was assessed for the degree of hepatic fibrosis. The results revealed that corilagin significantly reduced the expression of PPARγ, KLF4, SOCS1, p-STAT6, and TGF-β compared with model group and praziquantel administration (p < 0.01 or p < 0.05) in vivo and in vitro, which indicated a strong inhibitory effect of corilagin on IL-13Rα1 signaling pathway. As well, the inhibitory effect of corilagin showed a significant dose-dependence (p < 0.05). The area of fibrosis and distribution of M2 macrophages in mouse liver tissue were reduced significantly and dose-dependently with corilagin treatment compared to model group or praziquantel administration (p < 0.01 or p < 0.05), indicating that corilagin suppressed IL-13Rα1 signaling pathway and M2 macrophage polarization effectively in vivo. Furthermore, the anti-fibrogenic effect persisted even when IL-13Rα1 was up- or down-regulated in vitro. In conclusion, corilagin can suppress schistosome egg-induced hepatic fibrosis via inhibition of M2 macrophage polarization in the IL-13Rα1 signaling pathway.

Highlights

Schistosomiasis is an ancient parasitic disease that imposes a considerable economic and health burden, disabling more than it kills
The levels of Peroxisome proliferator-activated receptor gamma (PPARγ), Krüppel-like factor4 (KLF4), Suppressor of cytokine signaling 1 (SOCS1), and p-Signal transducer and activator of transcription 6 (STAT6) in the model experimental groups were increased compared with levels in the control group (p < 0.01, Student’s t-test, n = 3), which revealed the model is successful and the expression of these molecules increased with IL-13 stimulation
The levels decreased with increasing concentrations of corilagin (p < 0.05, one-way Analysis of variance (ANOVA), post-hoc: S-N-K method, n = 3), which confirmed a dose-dependent inhibitory effect of corilagin on the cytokines in IL-13Rα1 signaling pathway in vitro

Summary

Introduction

Schistosomiasis is an ancient parasitic disease that imposes a considerable economic and health burden, disabling more than it kills. IL-13 was demonstrated to be detrimental in schistosomiasis (Fallon et al, 2000) It is a key cytokine which strongly induced the expression of pro-fibrotic cytokines and M2 macrophage polarization via the IL-13α1 signaling pathway (Liu et al, 2012; Sica and Mantovani, 2012; Song and Wu, 2015). IL-13 binding the IL-4Rα/IL-13Rα1 receptor complex triggers signal transduction and increases the expression of PPARγ, KLF4 and SOCS1 (Biswas et al, 2012; Sica and Mantovani, 2012) These M2 cytokines stimulate the Kupffer cells and hepatic stellar cells to produce TGF-β, a crucial factor in fibrosis, and accelerate fibrosis progression (Fabregat et al, 2016). Inhibition of M2 polarization of macrophages and IL-13Rα1 signaling pathway may be the key to suppressing schistosomiasis hepatic fibrosis

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