| Loss of Discoidin Domain Receptor 2 Promotes Hepatic Fibrosis after Chronic Carbon Tetrachloride Through Altered Paracrine Interactions between Hepatic Stellate Cells and Liver-Associated Macrophages. | |
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MedLine Citation:
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PMID: 22019896 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Hepatic stellate cells (HSCs) interact with fibrillar collagen through the discoidin domain receptor 2 (DDR) in acute hepatic injury, generating increased fibrosis. However, the contribution of DDR2 signaling to chronic liver fibrosis in vivo is unclear, despite its relevance to chronic human liver disease. We administered carbon tetrachloride (CCl(4)) to DDR2(+/+) and DDR2(-/-) mice twice weekly, and liver tissues and isolated HSCs were analyzed. In contrast to changes seen in acute injury, after chronic CCl(4) administration, DDR2(-/-) livers had increased collagen deposition, gelatinolytic activity, and HSC density. Increased osteopontin, transforming growth factor-β1, monocyte chemoattractant protein-1, and IL-10, and reduced matrix metalloproteinase-2, matrix metalloproteinase-13, and collagen type I basal gene expression in quiescent DDR2(-/-) HSCs were amplified further after chronic CCl(4). In concordance, DDR2(-/-) HSCs isolated from chronically injured livers had enhanced in vitro migration and proliferation, but less extracellular matrix degradative activity. Macrophages from chronic CCl(4)-treated DDR2(-/-) livers showed stronger chemoattractive activity toward DDR2(-/-) HSCs than DDR2(+/+) macrophages, increased extracellular matrix degradation, and higher cytokine mRNA expression. In conclusion, loss of DDR2 promotes chronic liver fibrosis after CCl(4) injury. The fibrogenic sinusoidal milieu generated in chronic DDR2(-/-) livers recruits more HSCs to injured regions, which enhances fibrosis. Together, these findings suggest that normally DDR2 orchestrates gene programs and paracrine interactions between HSCs and macrophages that together attenuate chronic hepatic fibrosis. |
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Authors:
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Elvira Olaso; Beatriz Arteta; Aitor Benedicto; Olatz Crende; Scott L Friedman |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-10-18 |
Journal Detail:
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Title: The American journal of pathology Volume: - ISSN: 1525-2191 ISO Abbreviation: - Publication Date: 2011 Oct |
Date Detail:
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Created Date: 2011-10-24 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0370502 Medline TA: Am J Pathol Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
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Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved. |
Affiliation:
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UPV/EHU School of Medicine and Dentistry, Leioa, Spain; Division of Liver Diseases, Mount Sinai School of Medicine, New York. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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