Cleavage of Type I Collagen by Fibroblast Activation Protein-α Enhances Class A Scavenger Receptor Mediated Macrophage Adhesion
Pathophysiological conditions such as fibrosis, inflammation, and tumor progression are associated with modification of the extracellular matrix (ECM). These modifications create ligands that differentially interact with cells to promote responses that drive pathological processes. Within the tumor...
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| description | Pathophysiological conditions such as fibrosis, inflammation, and tumor progression are associated with modification of the extracellular matrix (ECM). These modifications create ligands that differentially interact with cells to promote responses that drive pathological processes. Within the tumor stroma, fibroblasts are activated and increase the expression of type I collagen. In addition, activated fibroblasts specifically express fibroblast activation protein-α (FAP), a post-prolyl peptidase. Although FAP reportedly cleaves type I collagen and contributes to tumor progression, the specific pathophysiologic role of FAP is not clear. In this study, the possibility that FAP-mediated cleavage of type I collagen modulates macrophage interaction with collagen was examined using macrophage adhesion assays. Our results demonstrate that FAP selectively cleaves type I collagen resulting in increased macrophage adhesion. Increased macrophage adhesion to FAP-cleaved collagen was not affected by inhibiting integrin-mediated interactions, but was abolished in macrophages lacking the class A scavenger receptor (SR-A/CD204). Further, SR-A expressing macrophages localize with activated fibroblasts in breast tumors of MMTV-PyMT mice. Together, these results demonstrate that FAP-cleaved collagen is a substrate for SR-A-dependent macrophage adhesion, and suggest that by modifying the ECM, FAP plays a novel role in mediating communication between activated fibroblasts and macrophages. |
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These modifications create ligands that differentially interact with cells to promote responses that drive pathological processes. Within the tumor stroma, fibroblasts are activated and increase the expression of type I collagen. In addition, activated fibroblasts specifically express fibroblast activation protein-α (FAP), a post-prolyl peptidase. Although FAP reportedly cleaves type I collagen and contributes to tumor progression, the specific pathophysiologic role of FAP is not clear. In this study, the possibility that FAP-mediated cleavage of type I collagen modulates macrophage interaction with collagen was examined using macrophage adhesion assays. Our results demonstrate that FAP selectively cleaves type I collagen resulting in increased macrophage adhesion. Increased macrophage adhesion to FAP-cleaved collagen was not affected by inhibiting integrin-mediated interactions, but was abolished in macrophages lacking the class A scavenger receptor (SR-A/CD204). Further, SR-A expressing macrophages localize with activated fibroblasts in breast tumors of MMTV-PyMT mice. Together, these results demonstrate that FAP-cleaved collagen is a substrate for SR-A-dependent macrophage adhesion, and suggest that by modifying the ECM, FAP plays a novel role in mediating communication between activated fibroblasts and macrophages.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0150287</identifier><identifier>PMID: 26934296</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adhesion ; Animals ; Biology and Life Sciences ; Breast - metabolism ; Breast - pathology ; Breast cancer ; Breast Neoplasms - metabolism ; Breast Neoplasms - pathology ; Cancer ; Cell activation ; Cell Adhesion ; Cells, Cultured ; Cleavage ; Collagen ; Collagen (type I) ; Collagen Type I - metabolism ; Cytokines ; Extracellular matrix ; Female ; Fibroblast activation protein ; Fibroblasts ; Fibrosis ; Gelatinases - metabolism ; Growth factors ; Humans ; Integrins - metabolism ; Interdisciplinary aspects ; Laboratories ; Macrophages ; Macrophages - cytology ; Macrophages - metabolism ; Macrophages - pathology ; Medicine and Health Sciences ; Membrane Proteins - metabolism ; Mice, Inbred C57BL ; Peptidase ; Proteins ; Recombinant Proteins - metabolism ; Research and Analysis Methods ; Scavenger receptors ; Scavenger Receptors, Class A - metabolism ; Serine Endopeptidases - metabolism ; Stroma ; Substrates ; Tumors</subject><ispartof>PloS one, 2016-03, Vol.11 (3), p.e0150287-e0150287</ispartof><rights>2016 Mazur et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Mazur, Anna</au><au>Holthoff, Emily</au><au>Vadali, Shanthi</au><au>Kelly, Thomas</au><au>Post, Steven R</au><au>Engler, Adam J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Cleavage of Type I Collagen by Fibroblast Activation Protein-α Enhances Class A Scavenger Receptor Mediated Macrophage Adhesion</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2016-03-02</date><risdate>2016</risdate><volume>11</volume><issue>3</issue><spage>e0150287</spage><epage>e0150287</epage><pages>e0150287-e0150287</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Pathophysiological conditions such as fibrosis, inflammation, and tumor progression are associated with modification of the extracellular matrix (ECM). These modifications create ligands that differentially interact with cells to promote responses that drive pathological processes. Within the tumor stroma, fibroblasts are activated and increase the expression of type I collagen. In addition, activated fibroblasts specifically express fibroblast activation protein-α (FAP), a post-prolyl peptidase. Although FAP reportedly cleaves type I collagen and contributes to tumor progression, the specific pathophysiologic role of FAP is not clear. In this study, the possibility that FAP-mediated cleavage of type I collagen modulates macrophage interaction with collagen was examined using macrophage adhesion assays. Our results demonstrate that FAP selectively cleaves type I collagen resulting in increased macrophage adhesion. Increased macrophage adhesion to FAP-cleaved collagen was not affected by inhibiting integrin-mediated interactions, but was abolished in macrophages lacking the class A scavenger receptor (SR-A/CD204). Further, SR-A expressing macrophages localize with activated fibroblasts in breast tumors of MMTV-PyMT mice. Together, these results demonstrate that FAP-cleaved collagen is a substrate for SR-A-dependent macrophage adhesion, and suggest that by modifying the ECM, FAP plays a novel role in mediating communication between activated fibroblasts and macrophages.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>26934296</pmid><doi>10.1371/journal.pone.0150287</doi><oa>free_for_read</oa></addata></record> |
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| subjects | Adhesion Animals Biology and Life Sciences Breast - metabolism Breast - pathology Breast cancer Breast Neoplasms - metabolism Breast Neoplasms - pathology Cancer Cell activation Cell Adhesion Cells, Cultured Cleavage Collagen Collagen (type I) Collagen Type I - metabolism Cytokines Extracellular matrix Female Fibroblast activation protein Fibroblasts Fibrosis Gelatinases - metabolism Growth factors Humans Integrins - metabolism Interdisciplinary aspects Laboratories Macrophages Macrophages - cytology Macrophages - metabolism Macrophages - pathology Medicine and Health Sciences Membrane Proteins - metabolism Mice, Inbred C57BL Peptidase Proteins Recombinant Proteins - metabolism Research and Analysis Methods Scavenger receptors Scavenger Receptors, Class A - metabolism Serine Endopeptidases - metabolism Stroma Substrates Tumors |
| title | Cleavage of Type I Collagen by Fibroblast Activation Protein-α Enhances Class A Scavenger Receptor Mediated Macrophage Adhesion |
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