IL-33 Involved in the Progression of Liver Fibrosis Through Innate Immunity Cells (Mφ) Regulated by ICOS/ICOSL Signaling in Early Stage of Mice Schistosomiasis

Abstract

AbstractSchistosomiasis liver fibrosis is characterized by the foci of a classical type 2 granulomatous inflammation in response to egg soluble antigen. The inducible costimulator (ICOS)/ICOSL signaling can mediate Th2 polarization and regulate the disease process of chronic schistosomiasis by adaptive immune response. ICOS/ICOSL signaling could regulate innate immune cells, including B cells and macrophage (Mφ), and participate in pulmonary fibrosis. The purpose of the study was to identify whether ICOS/ICOSL signaling could regulate the polarization of Mφ, and to explore the potential role of IL-33 in ICOSL knockout (ICOSL-KO) mice with schistosomiasis. Firstly, the expression level of CD86, CD206 and IL-33 was checked respectively in ICOSL-KO and WT mice infected with Schistosoma japonicum (S. japonicum). Then recombinant IL-33 (rIL-33) was injected into ICOSL-KO mice infected with S. japonicum. Our experiments showed that the liver Mφ was successfully polarized toward to classical activated Mφ (M1) and the expression of IL-33 was inhibited in ICOSL-KO mice. Furthermore, the injection of rIL-33 successfully aggravated liver fibrosis in ICOSL-KO mice, increased the numbers of lymphocyte antigen 6C (Ly6C)hi, enhanced the expression of C-C chemokine ligand (CCL)2,, CCL5 and C-X-C motif chemokine 2 (CXCL2), and promoted polarization of T helper (Th) cells to Th2 cells, as well as induced the autophagy and apoptosis of hepatic stellate cells (HSCs). Overall, the liver fibrosis was alleviated in ICOSL-KO mice along with the reduced expression of IL-33, which could skew the polarization of Mφ toward to M1, induce Th cells activation, HSCs apoptosis and autophagy through Smad2/3 and TGF-β signaling pathway, thus participated in the homeostasis of liver fibrosis of schistosomiasis.