TY - JOUR
T1 - Peroxidasin Deficiency Re-programs Macrophages Toward Pro-fibrolysis Function and Promotes Collagen Resolution in Liver
AU - Sojoodi, Mozhdeh
AU - Erstad, Derek J.
AU - Barrett, Stephen C.
AU - Salloum, Shadi
AU - Zhu, Shijia
AU - Qian, Tongqi
AU - Colon, Selene
AU - Gale, Eric M.
AU - Jordan, Veronica Clavijo
AU - Wang, Yongtao
AU - Li, Shen
AU - Ataeinia, Bahar
AU - Jalilifiroozinezhad, Sasan
AU - Lanuti, Michael
AU - Zukerberg, Lawrence
AU - Caravan, Peter
AU - Hoshida, Yujin
AU - Chung, Raymond T.
AU - Bhave, Gautam
AU - Lauer, Georg M.
AU - Fuchs, Bryan C.
AU - Tanabe, Kenneth K.
N1 - Funding Information:
The authors thank Dr Yuri Popov for his helpful advice regarding the collagen stabilization assay. The authors also thank Dr Byeong-Moo Kim for his helpful discussions and technical advice regarding the isolation of mouse primary stellate cell isolation. Mozhdeh Sojoodi, PhD (Conceptualization: Lead; Data curation: Lead; Formal analysis: Lead; Investigation: Lead; Methodology: Lead; Validation: Lead; Writing ? original draft: Lead), Derek J. Erstad, MD (Conceptualization: Supporting; Writing ? review & editing: Supporting), Stephen C. Barrett, BSc (Data curation: Supporting; Methodology: Supporting; Writing ? review & editing: Supporting), Shadi Salloum, MD, PhD (Data curation: Supporting), Shijia Zhu, PhD (Formal analysis: Supporting), Tongqi Qian, PhD (Formal analysis: Supporting), Selene Colon, PhD (Formal analysis: Supporting), Eric M Gale, PhD (Data curation: Supporting; Funding acquisition: Supporting), Veronica Clavijo Jordan, PhD (Formal analysis: Supporting), Yongtao Wang, PhD (Data curation: Supporting), Shen Li, MD (Formal analysis: Supporting), Bahar Ataeinia, MD (Data curation: Supporting), Sasan Jalilifiroozinezhad, PhD (Formal analysis: Supporting), Michael Lanuti, MD (Conceptualization: Supporting; Funding acquisition: Supporting; Supervision: Supporting), Lawrence Zukerberg, MD (Supervision: Supporting), Peter Caravan, PhD (Formal analysis: Supporting), Yujin Hoshida, MD, PhD (Formal analysis: Supporting; Supervision: Supporting), Raymond T. Chung, MD (Conceptualization: Supporting; Funding acquisition: Supporting; Supervision: Supporting), Gautam Bhave, MD (Conceptualization: Supporting; Funding acquisition: Supporting; Resources: Supporting; Validation: Supporting; Writing ? review & editing: Supporting), Georg Lauer, MD, PhD (Formal analysis: Supporting; Methodology: Supporting), Bryan C. Fuchs, PhD (Conceptualization: Supporting; Investigation: Supporting; Methodology: Supporting; Supervision: Supporting), Kenneth K. Tanabe, MD (Conceptualization: Supporting; Data curation: Supporting; Funding acquisition: Lead; Supervision: Lead; Writing ? review & editing: Lead)
Funding Information:
Funding Eric M. Gale was supported by National Institutes of Health (NIH) R01DK120663. Gautam Bhave was supported by NIH R01DK116964. Kenneth K. Tanabe was supported by NIH R01DK104956. Raymond Chung was supported by NIH R01DK108370, R01AI136715, and the Massachusetts General Hospital Research Scholars Program.
Publisher Copyright:
© 2022 The Authors
PY - 2022
Y1 - 2022
N2 - 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.
AB - 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.
KW - Fibrosis
KW - Liver
KW - Macrophages
KW - Peroxidasin
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U2 - 10.1016/j.jcmgh.2022.01.015
DO - 10.1016/j.jcmgh.2022.01.015
M3 - Article
C2 - 35093588
AN - SCOPUS:85127363678
JO - Cellular and Molecular Gastroenterology and Hepatology
JF - Cellular and Molecular Gastroenterology and Hepatology
SN - 2352-345X
ER -