Peroxidasin Deficiency Re-programs Macrophages Toward Pro-fibrolysis Function and Promotes Collagen Resolution in Liver.

Autor:	Sojoodi M; Division of Gastrointestinal and Oncologic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts., Erstad DJ; Division of Gastrointestinal and Oncologic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts., Barrett SC; Division of Gastrointestinal and Oncologic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts., Salloum S; Liver Center, Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts., Zhu S; Liver Tumor Translational Research Program, Simmons 22 Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas., Qian T; Liver Tumor Translational Research Program, Simmons 22 Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas., Colon S; Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, Tennessee., Gale EM; Athinoula A. Martinos Center for Biomedical Imaging, Institute for Innovation in Imaging (i3), Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts., Jordan VC; Athinoula A. Martinos Center for Biomedical Imaging, Institute for Innovation in Imaging (i3), Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts., Wang Y; Division of Gastrointestinal and Oncologic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts., Li S; Division of Gastrointestinal and Oncologic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts., Ataeinia B; Athinoula A. Martinos Center for Biomedical Imaging, Institute for Innovation in Imaging (i3), Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts., Jalilifiroozinezhad S; Koch Institute for Integrative Cancer Research, MIT, Cambridge, Massachusetts., Lanuti M; Division of Thoracic Surgery, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts., Zukerberg L; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts., Caravan P; Athinoula A. Martinos Center for Biomedical Imaging, Institute for Innovation in Imaging (i3), Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts., Hoshida Y; Liver Tumor Translational Research Program, Simmons 22 Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas., Chung RT; Liver Center, Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts., Bhave G; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts., Lauer GM; Liver Center, Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts., Fuchs BC; Division of Gastrointestinal and Oncologic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts., Tanabe KK; Division of Gastrointestinal and Oncologic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. Electronic address: ktanabe@partners.org.
Jazyk:	angličtina
Zdroj:	Cellular and molecular gastroenterology and hepatology [Cell Mol Gastroenterol Hepatol] 2022; Vol. 13 (5), pp. 1483-1509. Date of Electronic Publication: 2022 Jan 28.
DOI:	10.1016/j.jcmgh.2022.01.015
Abstrakt:	Background & Aims: During liver fibrosis, tissue repair mechanisms replace necrotic tissue with highly stabilized extracellular matrix proteins. Extracellular matrix stabilization influences the speed of tissue recovery. Here, we studied the expression and function of peroxidasin (PXDN), a peroxidase that uses hydrogen peroxide to cross-link collagen IV during liver fibrosis progression and regression. Methods: Mouse models of liver fibrosis and cirrhosis patients were analyzed for the expression of PXDN in liver and serum. Pxdn -/- and Pxdn +/+ mice were either treated with carbon tetrachloride for 6 weeks to generate toxin-induced fibrosis or fed with a choline-deficient L-amino acid-defined high-fat diet for 16 weeks to create nonalcoholic fatty liver disease fibrosis. Liver histology, quantitative real-time polymerase chain reaction, collagen content, flowcytometry and immunostaining of immune cells, RNA-sequencing, and liver function tests were analyzed. In vivo imaging of liver reactive oxygen species (ROS) was performed using a redox-active iron complex, Fe-PyC3A. Results: In human and mouse cirrhotic tissue, PXDN is expressed by stellate cells and is secreted into fibrotic areas. In patients with nonalcoholic fatty liver disease, serum levels of PXDN increased significantly. In both mouse models of liver fibrosis, PXDN deficiency resulted in elevated monocyte and pro-fibrolysis macrophage recruitment into fibrotic bands and caused decreased accumulation of cross-linked collagens. In Pxdn -/- mice, collagen fibers were loosely organized, an atypical phenotype that is reversible upon macrophage depletion. Elevated ROS in Pxdn -/- livers was observed, which can result in activation of hypoxic signaling cascades and may affect signaling pathways involved in macrophage polarization such as TNF-a via NF-kB. Fibrosis resolution in Pxdn -/- mice was associated with significant decrease in collagen content and improved liver function. Conclusion: PXDN deficiency is associated with increased ROS levels and a hypoxic liver microenvironment that can regulate recruitment and programming of pro-resolution macrophages. Our data implicate the importance of the liver microenvironment in macrophage programming during liver fibrosis and suggest a novel pathway that is involved in the resolution of scar tissue. (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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