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OPN‐a induces muscle inflammation by increasing recruitment and activation of pro‐inflammatory macrophages
NEW FINDINGS: What is the central question of this study? What is the functional relevance of OPN isoform expression in muscle pathology? What is the main finding and its importance? The full‐length human OPN‐a isoform is the most pro‐inflammatory isoform in the muscle microenvironment, acting on ma...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5095808/ https://www.ncbi.nlm.nih.gov/pubmed/27452303 http://dx.doi.org/10.1113/EP085768 |
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author | Many, Gina M. Yokosaki, Yasuyuki Uaesoontrachoon, Kitipong Nghiem, Peter P. Bello, Luca Dadgar, Sherry Yin, Ying Damsker, Jesse M. Cohen, Heather B. Kornegay, Joe N. Bamman, Marcas M. Mosser, David M. Nagaraju, Kanneboyina Hoffman, Eric P. |
author_facet | Many, Gina M. Yokosaki, Yasuyuki Uaesoontrachoon, Kitipong Nghiem, Peter P. Bello, Luca Dadgar, Sherry Yin, Ying Damsker, Jesse M. Cohen, Heather B. Kornegay, Joe N. Bamman, Marcas M. Mosser, David M. Nagaraju, Kanneboyina Hoffman, Eric P. |
author_sort | Many, Gina M. |
collection | PubMed |
description | NEW FINDINGS: What is the central question of this study? What is the functional relevance of OPN isoform expression in muscle pathology? What is the main finding and its importance? The full‐length human OPN‐a isoform is the most pro‐inflammatory isoform in the muscle microenvironment, acting on macrophages and myoblasts in an RGD‐integrin‐dependent manner. OPN‐a upregulates expression of tenascin‐C (TNC), a known Toll‐like receptor 4 (TLR4) agonist. Blocking TLR4 signalling inhibits the pro‐inflammatory effects of OPN‐a, suggesting that a potential mechanism of OPN action is by promoting TNC–TLR4 signalling. Although osteopontin (OPN) is an important mediator of muscle remodelling in health and disease, functional differences in human spliced OPN variants in the muscle microenvironment have not been characterized. We thus sought to define the pro‐inflammatory activities of human OPN isoforms (OPN‐a, OPN‐b and OPN‐c) on cells present in regenerating muscle. OPN transcripts were quantified in normal and dystrophic human and dog muscle. Human macrophages and myoblasts were stimulated with recombinant human OPN protein isoforms, and cytokine mRNA and protein induction was assayed. OPN isoforms were greatly increased in dystrophic human (OPN‐a > OPN‐b > OPN‐c) and dog muscle (OPN‐a = OPN‐c). In healthy human muscle, mechanical loading also upregulated OPN‐a expression (eightfold; P < 0.01), but did not significantly upregulate OPN‐c expression (twofold; P > 0.05). In vitro, OPN‐a displayed the most pronounced pro‐inflammatory activity among isoforms, acting on both macrophages and myoblasts. In vitro and in vivo data revealed that OPN‐a upregulated tenascin‐C (TNC), a known Toll‐like receptor 4 (TLR4) agonist. Inhibition of TLR4 signalling attenuated OPN‐mediated macrophage cytokine production. In summary, OPN‐a is the most abundant and functionally active human spliced isoform in the skeletal muscle microenvironment. Here, OPN‐a promotes pro‐inflammatory signalling in both macrophages and myoblasts, possibly through induction of TNC–TLR4 signalling. Together, our findings suggest that specific targeting of OPN‐a and/or TNC signalling in the damaged muscle microenvironment may be of therapeutic relevance. |
format | Online Article Text |
id | pubmed-5095808 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-50958082016-11-09 OPN‐a induces muscle inflammation by increasing recruitment and activation of pro‐inflammatory macrophages Many, Gina M. Yokosaki, Yasuyuki Uaesoontrachoon, Kitipong Nghiem, Peter P. Bello, Luca Dadgar, Sherry Yin, Ying Damsker, Jesse M. Cohen, Heather B. Kornegay, Joe N. Bamman, Marcas M. Mosser, David M. Nagaraju, Kanneboyina Hoffman, Eric P. Exp Physiol Research Papers NEW FINDINGS: What is the central question of this study? What is the functional relevance of OPN isoform expression in muscle pathology? What is the main finding and its importance? The full‐length human OPN‐a isoform is the most pro‐inflammatory isoform in the muscle microenvironment, acting on macrophages and myoblasts in an RGD‐integrin‐dependent manner. OPN‐a upregulates expression of tenascin‐C (TNC), a known Toll‐like receptor 4 (TLR4) agonist. Blocking TLR4 signalling inhibits the pro‐inflammatory effects of OPN‐a, suggesting that a potential mechanism of OPN action is by promoting TNC–TLR4 signalling. Although osteopontin (OPN) is an important mediator of muscle remodelling in health and disease, functional differences in human spliced OPN variants in the muscle microenvironment have not been characterized. We thus sought to define the pro‐inflammatory activities of human OPN isoforms (OPN‐a, OPN‐b and OPN‐c) on cells present in regenerating muscle. OPN transcripts were quantified in normal and dystrophic human and dog muscle. Human macrophages and myoblasts were stimulated with recombinant human OPN protein isoforms, and cytokine mRNA and protein induction was assayed. OPN isoforms were greatly increased in dystrophic human (OPN‐a > OPN‐b > OPN‐c) and dog muscle (OPN‐a = OPN‐c). In healthy human muscle, mechanical loading also upregulated OPN‐a expression (eightfold; P < 0.01), but did not significantly upregulate OPN‐c expression (twofold; P > 0.05). In vitro, OPN‐a displayed the most pronounced pro‐inflammatory activity among isoforms, acting on both macrophages and myoblasts. In vitro and in vivo data revealed that OPN‐a upregulated tenascin‐C (TNC), a known Toll‐like receptor 4 (TLR4) agonist. Inhibition of TLR4 signalling attenuated OPN‐mediated macrophage cytokine production. In summary, OPN‐a is the most abundant and functionally active human spliced isoform in the skeletal muscle microenvironment. Here, OPN‐a promotes pro‐inflammatory signalling in both macrophages and myoblasts, possibly through induction of TNC–TLR4 signalling. Together, our findings suggest that specific targeting of OPN‐a and/or TNC signalling in the damaged muscle microenvironment may be of therapeutic relevance. John Wiley and Sons Inc. 2016-09-24 2016-10-01 /pmc/articles/PMC5095808/ /pubmed/27452303 http://dx.doi.org/10.1113/EP085768 Text en © 2016 The Authors. Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs (http://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Research Papers Many, Gina M. Yokosaki, Yasuyuki Uaesoontrachoon, Kitipong Nghiem, Peter P. Bello, Luca Dadgar, Sherry Yin, Ying Damsker, Jesse M. Cohen, Heather B. Kornegay, Joe N. Bamman, Marcas M. Mosser, David M. Nagaraju, Kanneboyina Hoffman, Eric P. OPN‐a induces muscle inflammation by increasing recruitment and activation of pro‐inflammatory macrophages |
title | OPN‐a induces muscle inflammation by increasing recruitment and activation of pro‐inflammatory macrophages |
title_full | OPN‐a induces muscle inflammation by increasing recruitment and activation of pro‐inflammatory macrophages |
title_fullStr | OPN‐a induces muscle inflammation by increasing recruitment and activation of pro‐inflammatory macrophages |
title_full_unstemmed | OPN‐a induces muscle inflammation by increasing recruitment and activation of pro‐inflammatory macrophages |
title_short | OPN‐a induces muscle inflammation by increasing recruitment and activation of pro‐inflammatory macrophages |
title_sort | opn‐a induces muscle inflammation by increasing recruitment and activation of pro‐inflammatory macrophages |
topic | Research Papers |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5095808/ https://www.ncbi.nlm.nih.gov/pubmed/27452303 http://dx.doi.org/10.1113/EP085768 |
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