Paloma Ruiz-Blázquez , María Fernández-Fernández , Valeria Pistorio , Celia Martinez-Sanchez , Michele Costanzo , Paula Iruzubieta , Ekaterina Zhuravleva , Júlia Cacho-Pujol , Silvia Ariño , Alejandro Del Castillo-Cruz , Susana Núñez , Jesper B. Andersen , Margherita Ruoppolo , Javier Crespo , Carmen García-Ruiz , Luigi Michele Pavone , Thomas Reinheckel , Pau Sancho-Bru , Mar Coll , José C. Fernández-Checa , Anna Moles
{"title":"cathepsin d 对巨噬细胞的降解转移至关重要，而巨噬细胞的降解转移是解决肝纤维化所必需的。","authors":"Paloma Ruiz-Blázquez , María Fernández-Fernández , Valeria Pistorio , Celia Martinez-Sanchez , Michele Costanzo , Paula Iruzubieta , Ekaterina Zhuravleva , Júlia Cacho-Pujol , Silvia Ariño , Alejandro Del Castillo-Cruz , Susana Núñez , Jesper B. Andersen , Margherita Ruoppolo , Javier Crespo , Carmen García-Ruiz , Luigi Michele Pavone , Thomas Reinheckel , Pau Sancho-Bru , Mar Coll , José C. Fernández-Checa , Anna Moles","doi":"10.1016/j.molmet.2024.101989","DOIUrl":null,"url":null,"abstract":"<div><h3>Background and objectives</h3><p>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.</p></div><div><h3>Methods</h3><p>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.</p></div><div><h3>Results</h3><p>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<sup>ΔMyel</sup>) 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<sup>ΔMyel</sup> livers. Besides, CtsD<sup>ΔMyel</sup> liver macrophages displayed functional, phenotypical and secretomic changes, which resulted in a degradomic phenotypical shift, responsible for the defective proteolytic processing of collagen I <em>in vitro</em> and impaired collagen remodeling during fibrosis resolution <em>in vivo</em>. Finally, CtsD-expressing mononuclear phagocytes of cirrhotic human livers were enriched in lysosomal and ECM degradative signaling pathways.</p></div><div><h3>Conclusions</h3><p>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.</p></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"87 ","pages":"Article 101989"},"PeriodicalIF":7.0000,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2212877824001200/pdfft?md5=195eb12d948ef506074c6bad3375be3b&pid=1-s2.0-S2212877824001200-main.pdf","citationCount":"0","resultStr":"{\"title\":\"Cathepsin D is essential for the degradomic shift of macrophages required to resolve liver fibrosis\",\"authors\":\"Paloma Ruiz-Blázquez , María Fernández-Fernández , Valeria Pistorio , Celia Martinez-Sanchez , Michele Costanzo , Paula Iruzubieta , Ekaterina Zhuravleva , Júlia Cacho-Pujol , Silvia Ariño , Alejandro Del Castillo-Cruz , Susana Núñez , Jesper B. 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Herein, in this study we evaluate the role of macrophage-derived cathepsin D (CtsD) during liver fibrosis.</p></div><div><h3>Methods</h3><p>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.</p></div><div><h3>Results</h3><p>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<sup>ΔMyel</sup>) 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<sup>ΔMyel</sup> livers. Besides, CtsD<sup>ΔMyel</sup> liver macrophages displayed functional, phenotypical and secretomic changes, which resulted in a degradomic phenotypical shift, responsible for the defective proteolytic processing of collagen I <em>in vitro</em> and impaired collagen remodeling during fibrosis resolution <em>in vivo</em>. Finally, CtsD-expressing mononuclear phagocytes of cirrhotic human livers were enriched in lysosomal and ECM degradative signaling pathways.</p></div><div><h3>Conclusions</h3><p>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.</p></div>\",\"PeriodicalId\":18765,\"journal\":{\"name\":\"Molecular Metabolism\",\"volume\":\"87 \",\"pages\":\"Article 101989\"},\"PeriodicalIF\":7.0000,\"publicationDate\":\"2024-07-15\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.sciencedirect.com/science/article/pii/S2212877824001200/pdfft?md5=195eb12d948ef506074c6bad3375be3b&pid=1-s2.0-S2212877824001200-main.pdf\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Molecular Metabolism\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S2212877824001200\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"ENDOCRINOLOGY & METABOLISM\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Metabolism","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2212877824001200","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ENDOCRINOLOGY & METABOLISM","Score":null,"Total":0}
Cathepsin D is essential for the degradomic shift of macrophages required to resolve liver fibrosis
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 (CtsDΔMyel) 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 CtsDΔMyel livers. Besides, CtsDΔMyel 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.
期刊介绍：
Molecular Metabolism is a leading journal dedicated to sharing groundbreaking discoveries in the field of energy homeostasis and the underlying factors of metabolic disorders. These disorders include obesity, diabetes, cardiovascular disease, and cancer. Our journal focuses on publishing research driven by hypotheses and conducted to the highest standards, aiming to provide a mechanistic understanding of energy homeostasis-related behavior, physiology, and dysfunction.
We promote interdisciplinary science, covering a broad range of approaches from molecules to humans throughout the lifespan. Our goal is to contribute to transformative research in metabolism, which has the potential to revolutionize the field. By enabling progress in the prognosis, prevention, and ultimately the cure of metabolic disorders and their long-term complications, our journal seeks to better the future of health and well-being.
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