Cathepsin D is essential for the degradomic shift of macrophages required to resolve liver fibrosis.

Autor:	Ruiz-Blázquez P; Institute of Biomedical Research of Barcelona, Spanish National Research Council, Barcelona, Spain; CiberEHD, Spain; University of Barcelona, Barcelona, Spain; IDIBAPS, Barcelona, Spain., Fernández-Fernández M; Institute of Biomedical Research of Barcelona, Spanish National Research Council, Barcelona, Spain; CiberEHD, Spain; University of Barcelona, Barcelona, Spain; IDIBAPS, Barcelona, Spain., Pistorio V; Institute of Biomedical Research of Barcelona, Spanish National Research Council, Barcelona, Spain; Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy; Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine (CRSA), Paris, France., Martinez-Sanchez C; CiberEHD, Spain; University of Barcelona, Barcelona, Spain; IDIBAPS, Barcelona, Spain., Costanzo M; Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy; CEINGE-Biotecnologie Avanzate Franco Salvatore s.c.ar.l., Naples, Italy., Iruzubieta P; Department of Gastroenterology and Hepatology, Marqués de Valdecilla University Hospital, Research Institute Marqués de Valdecilla (IDIVAL), Santander, Spain., Zhuravleva E; Biotech Research and Innovation Centre (BRIC), Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; LEO Foundation Skin Immunology Research Center (SIC), Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Cacho-Pujol J; Institute of Biomedical Research of Barcelona, Spanish National Research Council, Barcelona, Spain; University of Barcelona, Barcelona, Spain; IDIBAPS, Barcelona, Spain., Ariño S; CiberEHD, Spain; University of Barcelona, Barcelona, Spain; IDIBAPS, Barcelona, Spain., Del Castillo-Cruz A; Institute of Biomedical Research of Barcelona, Spanish National Research Council, Barcelona, Spain., Núñez S; CiberEHD, Spain., Andersen JB; Biotech Research and Innovation Centre (BRIC), Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Ruoppolo M; Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy; CEINGE-Biotecnologie Avanzate Franco Salvatore s.c.ar.l., Naples, Italy., Crespo J; Department of Gastroenterology and Hepatology, Marqués de Valdecilla University Hospital, Research Institute Marqués de Valdecilla (IDIVAL), Santander, Spain., García-Ruiz C; Institute of Biomedical Research of Barcelona, Spanish National Research Council, Barcelona, Spain; CiberEHD, Spain; IDIBAPS, Barcelona, Spain; USC Research Center for ALPD, Los Angeles, United States; Associated Unit IIBB-IMIM, Barcelona, Spain., Pavone LM; Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy., Reinheckel T; Institute of Molecular Medicine and Cell Research, Faculty of Medicine, Albert-Ludwigs-University, Freiburg, Germany; German Cancer Consortium (DKTK), DKFZ Partner Site Freiburg, Germany; Center for Biological Signaling Studies BIOSS, University of Freiburg, Germany., Sancho-Bru P; CiberEHD, Spain; University of Barcelona, Barcelona, Spain; IDIBAPS, Barcelona, Spain., Coll M; CiberEHD, Spain; University of Barcelona, Barcelona, Spain; IDIBAPS, Barcelona, Spain; Medicine Department, Faculty of Medicine, University of Barcelona, Spain., Fernández-Checa JC; Institute of Biomedical Research of Barcelona, Spanish National Research Council, Barcelona, Spain; CiberEHD, Spain; IDIBAPS, Barcelona, Spain; USC Research Center for ALPD, Los Angeles, United States; Associated Unit IIBB-IMIM, Barcelona, Spain., Moles A; Institute of Biomedical Research of Barcelona, Spanish National Research Council, Barcelona, Spain; CiberEHD, Spain; IDIBAPS, Barcelona, Spain; Associated Unit IIBB-IMIM, Barcelona, Spain. Electronic address: ana.moles@iibb.csic.es.
Jazyk:	angličtina
Zdroj:	Molecular metabolism [Mol Metab] 2024 Sep; Vol. 87, pp. 101989. Date of Electronic Publication: 2024 Jul 15.
DOI:	10.1016/j.molmet.2024.101989
Abstrakt:	Background and Objectives: Fibrosis contributes to 45% of deaths in industrialized nations and is characterized by an abnormal accumulation of extracellular matrix (ECM). There are no specific anti-fibrotic treatments for liver fibrosis, and previous unsuccessful attempts at drug development have focused on preventing ECM deposition. Because liver fibrosis is largely acknowledged to be reversible, regulating fibrosis resolution could offer novel therapeutical options. However, little is known about the mechanisms controlling ECM remodeling during resolution. Changes in proteolytic activity are essential for ECM homeostasis and macrophages are an important source of proteases. Herein, in this study we evaluate the role of macrophage-derived cathepsin D (CtsD) during liver fibrosis. Methods: CtsD expression and associated pathways were characterized in single-cell RNA sequencing and transcriptomic datasets in human cirrhosis. Liver fibrosis progression, reversion and functional characterization were assessed in novel myeloid-CtsD and hepatocyte-CtsD knock-out mice. Results: Analysis of single-cell RNA sequencing datasets demonstrated CtsD was expressed in macrophages and hepatocytes in human cirrhosis. Liver fibrosis progression, reversion and functional characterization were assessed in novel myeloid-CtsD (CtsD ΔMyel ) and hepatocyte-CtsD knock-out mice. CtsD deletion in macrophages, but not in hepatocytes, resulted in enhanced liver fibrosis. Both inflammatory and matrisome proteomic signatures were enriched in fibrotic CtsD ΔMyel livers. Besides, CtsD ΔMyel liver macrophages displayed functional, phenotypical and secretomic changes, which resulted in a degradomic phenotypical shift, responsible for the defective proteolytic processing of collagen I in vitro and impaired collagen remodeling during fibrosis resolution in vivo. Finally, CtsD-expressing mononuclear phagocytes of cirrhotic human livers were enriched in lysosomal and ECM degradative signaling pathways. Conclusions: Our work describes for the first-time CtsD-driven lysosomal activity as a central hub for restorative macrophage function during fibrosis resolution and opens new avenues to explore their degradome landscape to inform drug development. Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. (Copyright © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)
Databáze:	MEDLINE
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