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TRPV4 Plays a Role in Matrix Stiffness-Induced Macrophage Polarization

Phenotypic polarization of macrophages is deemed essential in innate immunity and various pathophysiological conditions. We have now determined key aspects of the molecular mechanism by which mechanical cues regulate macrophage polarization. We show that Transient Receptor Potential Vanilloid 4 (TRP...

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Autores principales: Dutta, Bidisha, Goswami, Rishov, Rahaman, Shaik O.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7767862/
https://www.ncbi.nlm.nih.gov/pubmed/33381111
http://dx.doi.org/10.3389/fimmu.2020.570195
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author Dutta, Bidisha
Goswami, Rishov
Rahaman, Shaik O.
author_facet Dutta, Bidisha
Goswami, Rishov
Rahaman, Shaik O.
author_sort Dutta, Bidisha
collection PubMed
description Phenotypic polarization of macrophages is deemed essential in innate immunity and various pathophysiological conditions. We have now determined key aspects of the molecular mechanism by which mechanical cues regulate macrophage polarization. We show that Transient Receptor Potential Vanilloid 4 (TRPV4), a mechanosensitive ion channel, mediates substrate stiffness-induced macrophage polarization. Using atomic force microscopy, we showed that genetic ablation of TRPV4 function abrogated fibrosis-induced matrix stiffness generation in skin tissues. We have determined that stiffer skin tissue promotes the M1 macrophage subtype in a TRPV4-dependent manner; soft tissue does not. These findings were further validated by our in vitro results which showed that stiff matrix (50 kPa) alone increased expression of macrophage M1 markers in a TRPV4-dependent manner, and this response was further augmented by the addition of soluble factors; neither of which occurred with soft matrix (1 kPa). A direct requirement for TRPV4 in M1 macrophage polarization spectrum in response to increased stiffness was evident from results of gain-of-function assays, where reintroduction of TRPV4 significantly upregulated the expression of M1 markers in TRPV4 KO macrophages. Together, these data provide new insights regarding the role of TRPV4 in matrix stiffness-induced macrophage polarization spectrum that may be explored in tissue engineering and regenerative medicine and targeted therapeutics.
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spelling pubmed-77678622020-12-29 TRPV4 Plays a Role in Matrix Stiffness-Induced Macrophage Polarization Dutta, Bidisha Goswami, Rishov Rahaman, Shaik O. Front Immunol Immunology Phenotypic polarization of macrophages is deemed essential in innate immunity and various pathophysiological conditions. We have now determined key aspects of the molecular mechanism by which mechanical cues regulate macrophage polarization. We show that Transient Receptor Potential Vanilloid 4 (TRPV4), a mechanosensitive ion channel, mediates substrate stiffness-induced macrophage polarization. Using atomic force microscopy, we showed that genetic ablation of TRPV4 function abrogated fibrosis-induced matrix stiffness generation in skin tissues. We have determined that stiffer skin tissue promotes the M1 macrophage subtype in a TRPV4-dependent manner; soft tissue does not. These findings were further validated by our in vitro results which showed that stiff matrix (50 kPa) alone increased expression of macrophage M1 markers in a TRPV4-dependent manner, and this response was further augmented by the addition of soluble factors; neither of which occurred with soft matrix (1 kPa). A direct requirement for TRPV4 in M1 macrophage polarization spectrum in response to increased stiffness was evident from results of gain-of-function assays, where reintroduction of TRPV4 significantly upregulated the expression of M1 markers in TRPV4 KO macrophages. Together, these data provide new insights regarding the role of TRPV4 in matrix stiffness-induced macrophage polarization spectrum that may be explored in tissue engineering and regenerative medicine and targeted therapeutics. Frontiers Media S.A. 2020-12-14 /pmc/articles/PMC7767862/ /pubmed/33381111 http://dx.doi.org/10.3389/fimmu.2020.570195 Text en Copyright © 2020 Dutta, Goswami and Rahaman http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Dutta, Bidisha
Goswami, Rishov
Rahaman, Shaik O.
TRPV4 Plays a Role in Matrix Stiffness-Induced Macrophage Polarization
title TRPV4 Plays a Role in Matrix Stiffness-Induced Macrophage Polarization
title_full TRPV4 Plays a Role in Matrix Stiffness-Induced Macrophage Polarization
title_fullStr TRPV4 Plays a Role in Matrix Stiffness-Induced Macrophage Polarization
title_full_unstemmed TRPV4 Plays a Role in Matrix Stiffness-Induced Macrophage Polarization
title_short TRPV4 Plays a Role in Matrix Stiffness-Induced Macrophage Polarization
title_sort trpv4 plays a role in matrix stiffness-induced macrophage polarization
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7767862/
https://www.ncbi.nlm.nih.gov/pubmed/33381111
http://dx.doi.org/10.3389/fimmu.2020.570195
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