LOXL2 Inhibition Paves the Way for Macrophage-Mediated Collagen Degradation in Liver Fibrosis
Liver fibrosis is characterized by the excessive accumulation of extracellular matrix (ECM) proteins and enzymes, especially fibrillary collagens, and represents a major cause of morbidity and mortality worldwide. Lysyl oxidases (LOXs) drive covalent crosslinking of collagen fibers, thereby promotin...
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Frontiers Media S.A.
2020-03-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2020.00480/full |
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| author | Mordehay Klepfish Tamar Gross Milena Vugman Nikolaos A. Afratis Sapir Havusha-Laufer Eli Brazowski Inna Solomonov Chen Varol Chen Varol Irit Sagi |
| author_facet | Mordehay Klepfish Tamar Gross Milena Vugman Nikolaos A. Afratis Sapir Havusha-Laufer Eli Brazowski Inna Solomonov Chen Varol Chen Varol Irit Sagi |
| author_sort | Mordehay Klepfish |
| collection | DOAJ |
| description | Liver fibrosis is characterized by the excessive accumulation of extracellular matrix (ECM) proteins and enzymes, especially fibrillary collagens, and represents a major cause of morbidity and mortality worldwide. Lysyl oxidases (LOXs) drive covalent crosslinking of collagen fibers, thereby promoting stabilization and accumulation of liver fibrosis while limiting its resolution. Here we show in a carbon tetrachloride (CCl4)-induced liver fibrosis murine model that treatment with a novel anti-lysyl oxidase like 2 (LOXL2) neutralizing antibody, which targets extracellular LOXL2, significantly improves fibrosis resolution. LOXL2 inhibition following the onset of fibrosis accelerated and augmented collagen degradation. This was accompanied by increased localization of reparative monocyte-derived macrophages (MoMFs) in the proximity of fibrotic fibers and their representation in the liver. These cells secreted collagenolytic matrix metalloproteinases (MMPs) and, in particular, the membrane-bound MT1-MMP (MMP-14) collagenase. Inducible and selective ablation of infiltrating MoMFs negated the increased “on-fiber” accumulation of MMP-14-expressing MoMFs and the accelerated collagenolytic activity observed in the anti-LOXL2-treated mice. Many studies of liver fibrosis focus on preventing the progression of the fibrotic process. In contrast, the therapeutic mechanism of LOXL2 inhibition presented herein aims at reversing existing fibrosis and facilitating endogenous liver regeneration by paving the way for collagenolytic macrophages. |
| first_indexed | 2024-12-11T23:16:38Z |
| format | Article |
| id | doaj.art-83cb3c671bac499ca08859b5d75d220c |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-11T23:16:38Z |
| publishDate | 2020-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-83cb3c671bac499ca08859b5d75d220c2022-12-22T00:46:30ZengFrontiers Media S.A.Frontiers in Immunology1664-32242020-03-011110.3389/fimmu.2020.00480502348LOXL2 Inhibition Paves the Way for Macrophage-Mediated Collagen Degradation in Liver FibrosisMordehay Klepfish0Tamar Gross1Milena Vugman2Nikolaos A. Afratis3Sapir Havusha-Laufer4Eli Brazowski5Inna Solomonov6Chen Varol7Chen Varol8Irit Sagi9Department of Biological Regulation, Weizmann Institute of Science, Rehovot, IsraelDepartment of Biological Regulation, Weizmann Institute of Science, Rehovot, IsraelResearch Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center, Tel Aviv-Yafo, IsraelDepartment of Biological Regulation, Weizmann Institute of Science, Rehovot, IsraelDepartment of Biological Regulation, Weizmann Institute of Science, Rehovot, IsraelResearch Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center, Tel Aviv-Yafo, IsraelDepartment of Biological Regulation, Weizmann Institute of Science, Rehovot, IsraelResearch Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center, Tel Aviv-Yafo, IsraelDepartment of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv-Yafo, IsraelDepartment of Biological Regulation, Weizmann Institute of Science, Rehovot, IsraelLiver fibrosis is characterized by the excessive accumulation of extracellular matrix (ECM) proteins and enzymes, especially fibrillary collagens, and represents a major cause of morbidity and mortality worldwide. Lysyl oxidases (LOXs) drive covalent crosslinking of collagen fibers, thereby promoting stabilization and accumulation of liver fibrosis while limiting its resolution. Here we show in a carbon tetrachloride (CCl4)-induced liver fibrosis murine model that treatment with a novel anti-lysyl oxidase like 2 (LOXL2) neutralizing antibody, which targets extracellular LOXL2, significantly improves fibrosis resolution. LOXL2 inhibition following the onset of fibrosis accelerated and augmented collagen degradation. This was accompanied by increased localization of reparative monocyte-derived macrophages (MoMFs) in the proximity of fibrotic fibers and their representation in the liver. These cells secreted collagenolytic matrix metalloproteinases (MMPs) and, in particular, the membrane-bound MT1-MMP (MMP-14) collagenase. Inducible and selective ablation of infiltrating MoMFs negated the increased “on-fiber” accumulation of MMP-14-expressing MoMFs and the accelerated collagenolytic activity observed in the anti-LOXL2-treated mice. Many studies of liver fibrosis focus on preventing the progression of the fibrotic process. In contrast, the therapeutic mechanism of LOXL2 inhibition presented herein aims at reversing existing fibrosis and facilitating endogenous liver regeneration by paving the way for collagenolytic macrophages.https://www.frontiersin.org/article/10.3389/fimmu.2020.00480/fullliver macrophageslysyl oxidase like 2 (LOXL2)liver fibrosismatrix metalloproteinases (MMPs)matrix metalloproteinase-14 (MMP-14)monocyte-derived macrophages |
| spellingShingle | Mordehay Klepfish Tamar Gross Milena Vugman Nikolaos A. Afratis Sapir Havusha-Laufer Eli Brazowski Inna Solomonov Chen Varol Chen Varol Irit Sagi LOXL2 Inhibition Paves the Way for Macrophage-Mediated Collagen Degradation in Liver Fibrosis Frontiers in Immunology liver macrophages lysyl oxidase like 2 (LOXL2) liver fibrosis matrix metalloproteinases (MMPs) matrix metalloproteinase-14 (MMP-14) monocyte-derived macrophages |
| title | LOXL2 Inhibition Paves the Way for Macrophage-Mediated Collagen Degradation in Liver Fibrosis |
| title_full | LOXL2 Inhibition Paves the Way for Macrophage-Mediated Collagen Degradation in Liver Fibrosis |
| title_fullStr | LOXL2 Inhibition Paves the Way for Macrophage-Mediated Collagen Degradation in Liver Fibrosis |
| title_full_unstemmed | LOXL2 Inhibition Paves the Way for Macrophage-Mediated Collagen Degradation in Liver Fibrosis |
| title_short | LOXL2 Inhibition Paves the Way for Macrophage-Mediated Collagen Degradation in Liver Fibrosis |
| title_sort | loxl2 inhibition paves the way for macrophage mediated collagen degradation in liver fibrosis |
| topic | liver macrophages lysyl oxidase like 2 (LOXL2) liver fibrosis matrix metalloproteinases (MMPs) matrix metalloproteinase-14 (MMP-14) monocyte-derived macrophages |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2020.00480/full |
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