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Mechanotransduction via a TRPV4-Rac1 signaling axis plays a role in multinucleated giant cell formation

Multinucleated giant cells are formed by the fusion of macrophages and are a characteristic feature in numerous pathophysiological conditions including the foreign body response (FBR). Foreign body giant cells (FBGCs) are inflammatory and destructive multinucleated macrophages and may cause damage a...

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Autores principales: Arya, Rakesh K., Goswami, Rishov, Rahaman, Shaik O.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Biochemistry and Molecular Biology 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948992/
https://www.ncbi.nlm.nih.gov/pubmed/33262217
http://dx.doi.org/10.1074/jbc.RA120.014597
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author Arya, Rakesh K.
Goswami, Rishov
Rahaman, Shaik O.
author_facet Arya, Rakesh K.
Goswami, Rishov
Rahaman, Shaik O.
author_sort Arya, Rakesh K.
collection PubMed
description Multinucleated giant cells are formed by the fusion of macrophages and are a characteristic feature in numerous pathophysiological conditions including the foreign body response (FBR). Foreign body giant cells (FBGCs) are inflammatory and destructive multinucleated macrophages and may cause damage and/or rejection of implants. However, while these features of FBGCs are well established, the molecular mechanisms underlying their formation remain elusive. Improved understanding of the molecular mechanisms underlying the formation of FBGCs may permit the development of novel implants that eliminate or reduce the FBR. Our previous study showed that transient receptor potential vanilloid 4 (TRPV4), a mechanosensitive ion channel/receptor, is required for FBGC formation and FBR to biomaterials. Here, we have determined that (a) TRPV4 is directly involved in fusogenic cytokine (interleukin-4 plus granulocyte macrophage–colony stimulating factor)–induced activation of Rac1, in bone marrow–derived macrophages; (b) TRPV4 directly interacts with Rac1, and their interaction is further augmented in the presence of fusogenic cytokines; (c) TRPV4-dependent activation of Rac1 is essential for the augmentation of intracellular stiffness and regulation of cytoskeletal remodeling; and (d) TRPV4-Rac1 signaling axis is critical in fusogenic cytokine–induced FBGC formation. Together, these data suggest a novel mechanism whereby a functional interaction between TRPV4 and Rac1 leads to cytoskeletal remodeling and intracellular stiffness generation to modulate FBGC formation.
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spelling pubmed-79489922021-03-19 Mechanotransduction via a TRPV4-Rac1 signaling axis plays a role in multinucleated giant cell formation Arya, Rakesh K. Goswami, Rishov Rahaman, Shaik O. J Biol Chem Research Article Multinucleated giant cells are formed by the fusion of macrophages and are a characteristic feature in numerous pathophysiological conditions including the foreign body response (FBR). Foreign body giant cells (FBGCs) are inflammatory and destructive multinucleated macrophages and may cause damage and/or rejection of implants. However, while these features of FBGCs are well established, the molecular mechanisms underlying their formation remain elusive. Improved understanding of the molecular mechanisms underlying the formation of FBGCs may permit the development of novel implants that eliminate or reduce the FBR. Our previous study showed that transient receptor potential vanilloid 4 (TRPV4), a mechanosensitive ion channel/receptor, is required for FBGC formation and FBR to biomaterials. Here, we have determined that (a) TRPV4 is directly involved in fusogenic cytokine (interleukin-4 plus granulocyte macrophage–colony stimulating factor)–induced activation of Rac1, in bone marrow–derived macrophages; (b) TRPV4 directly interacts with Rac1, and their interaction is further augmented in the presence of fusogenic cytokines; (c) TRPV4-dependent activation of Rac1 is essential for the augmentation of intracellular stiffness and regulation of cytoskeletal remodeling; and (d) TRPV4-Rac1 signaling axis is critical in fusogenic cytokine–induced FBGC formation. Together, these data suggest a novel mechanism whereby a functional interaction between TRPV4 and Rac1 leads to cytoskeletal remodeling and intracellular stiffness generation to modulate FBGC formation. American Society for Biochemistry and Molecular Biology 2020-12-04 /pmc/articles/PMC7948992/ /pubmed/33262217 http://dx.doi.org/10.1074/jbc.RA120.014597 Text en © 2020 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Research Article
Arya, Rakesh K.
Goswami, Rishov
Rahaman, Shaik O.
Mechanotransduction via a TRPV4-Rac1 signaling axis plays a role in multinucleated giant cell formation
title Mechanotransduction via a TRPV4-Rac1 signaling axis plays a role in multinucleated giant cell formation
title_full Mechanotransduction via a TRPV4-Rac1 signaling axis plays a role in multinucleated giant cell formation
title_fullStr Mechanotransduction via a TRPV4-Rac1 signaling axis plays a role in multinucleated giant cell formation
title_full_unstemmed Mechanotransduction via a TRPV4-Rac1 signaling axis plays a role in multinucleated giant cell formation
title_short Mechanotransduction via a TRPV4-Rac1 signaling axis plays a role in multinucleated giant cell formation
title_sort mechanotransduction via a trpv4-rac1 signaling axis plays a role in multinucleated giant cell formation
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948992/
https://www.ncbi.nlm.nih.gov/pubmed/33262217
http://dx.doi.org/10.1074/jbc.RA120.014597
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