Endothelin receptors promote schistosomiasis-induced hepatic fibrosis via splenic B cells

• Published in: PLoS pathogens 2020-10, Vol.16 (10), p.e1008947-e1008947
• Main Authors: Kong, Hongyan, He, Jinan, Guo, Shusen, Song, Qiqin, Xiang, Dandan, Tao, Ran, Yu, Haijing, Chen, Guang, Huang, Zhiyong, Ning, Qin, Huang, Jiaquan
• Format: Article
• Language: English
• Subjects: Adult; Aged; Animal models; Animals; B-Lymphocytes - metabolism; B-Lymphocytes - parasitology; B-Lymphocytes - pathology; Biology and Life Sciences; Biopsy; Care and treatment; Cell activation; Cell receptors; Chronic illnesses; Complications and side effects; Development and progression; Diameters; Eggs; Endothelin receptors; Endothelins; Female; Fibrosis; Fibrosis - etiology; Fibrosis - metabolism; Fibrosis - pathology; Humans; Hypertension; Infections; Infectious diseases; Interleukin; Interleukin 10; Liver; Liver diseases; Liver Diseases - etiology; Liver Diseases - metabolism; Liver Diseases - pathology; Lymphocytes B; Lymphocytes T; Male; Medical schools; Medicine and Health Sciences; Mice; Mice, Inbred C57BL; Middle Aged; Pathogenesis; Peptides; Portal vein; Receptors; Receptors, Endothelin - genetics; Receptors, Endothelin - metabolism; Research and Analysis Methods; Schistosoma japonicum - isolation & purification; Schistosomiasis; Schistosomiasis - complications; Schistosomiasis - parasitology; Smooth muscle; Spleen; Spleen - metabolism; Spleen - parasitology; Spleen - pathology; Splenomegaly; Tropical diseases; Vasoactive agents
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1008947

Endothelin receptors (ETRs) are activated by vasoactive peptide endothelins and involved in the pathogenesis of hepatic fibrosis. However, less is known about the role of ETRs in Schistosoma (S.) japonicum-induced hepatic fibrosis. Here, we show that the expression of ETRs is markedly enhanced in the liver and spleen tissues of patients with schistosome-induced fibrosis, as well as in murine models. Additional analyses have indicated that the expression levels of ETRs in schistosomiasis patients are highly correlated with the portal vein and spleen thickness diameter, both of which represent the severity of fibrosis. Splenomegaly is a characteristic symptom of schistosome infection, and splenic abnormality may promote the progression of hepatic fibrosis. We further demonstrate that elevated levels of ETRs are predominantly expressed on splenic B cells in spleen tissues during infection. Importantly, using a well-studied model of human schistosomiasis, we demonstrate that endothelin receptor antagonists can partially reverse schistosome-induced hepatic fibrosis by suppressing the activation of splenic B cells characterized by interleukin-10 (IL-10) secretion and regulatory T (Treg) cell-inducing capacity. Our study provides insights into the mechanisms by which ETRs regulate schistosomiasis hepatic fibrosis and highlights the potential of endothelin receptor antagonist as a therapeutic intervention for fibrotic diseases.