Endothelin receptors promote schistosomiasis-induced hepatic fibrosis via splenic B cells
| Autor: | Guang Chen, Qin Ning, Dandan Xiang, Zhiyong Huang, Hongyan Kong, Qiqin Song, Ran Tao, Jinan He, Jiaquan Huang, Shusen Guo, Haijing Yu |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Male
B Cells Physiology Schistosoma japonicum Endothelins Pathogenesis White Blood Cells Mice Medical Conditions Animal Cells Fibrosis Immune Physiology Medicine and Health Sciences Schistosomiasis Biology (General) Staining B-Lymphocytes 0303 health sciences Pharmaceutics Receptors Endothelin Liver Diseases 030302 biochemistry & molecular biology Animal Models Middle Aged medicine.anatomical_structure Experimental Organism Systems Helminth Infections Liver Fibrosis Female Cellular Types Endothelin receptor Research Article Neglected Tropical Diseases Adult medicine.hormone QH301-705.5 Immune Cells Immunology Mouse Models Spleen Gastroenterology and Hepatology Research and Analysis Methods Microbiology 03 medical and health sciences Model Organisms Drug Therapy Virology Parasitic Diseases Genetics medicine Animals Humans Antibody-Producing Cells Molecular Biology Aged 030304 developmental biology Blood Cells Ethidium Bromide Staining Endothelin receptor antagonist business.industry Biology and Life Sciences Cell Biology RC581-607 Tropical Diseases medicine.disease Mice Inbred C57BL Specimen Preparation and Treatment Animal Studies Cancer research Parasitology Immunologic diseases. Allergy Hepatic fibrosis business Receptor Antagonist Therapy Developmental Biology |
| Zdroj: | PLoS Pathogens, Vol 16, Iss 10, p e1008947 (2020) PLoS Pathogens |
| ISSN: | 1553-7374 1553-7366 |
| Popis: | 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. Author summary Schistosomiasis is a serious but neglected tropical infectious disease. which can lead to hepatic fibrosis and death. To date, there are still no approved antifibrotic therapies. Hepatic fibrosis results in portal hypertension and variceal bleeding, and it is the primary cause of mortality from schistosomiasis. Splenomegaly and hypersplenism can manifest following the development of portal hypertension. Accumulating evidence suggests that the spleen plays a critical role in the development of hepatic fibrosis. In this study, using Schistosoma (S.) japonicum in both humans and mice, we show that progressive hepatic schistosomiasis caused elevation of endothelin receptors (ETRs) both in liver and spleen tissues, and the endothelin receptor-producing cells are mainly located in splenic B cells. More importantly, we demonstrate that endothelin receptor antagonists can partially reverse schistosome-induced hepatic fibrosis by suppressing the activation of splenic B cells during infection. Thus, our study highlights the potential of endothelin receptor antagonist as a therapeutic intervention for schistosomiasis and other fibrotic diseases. |
| Databáze: | OpenAIRE |
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