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A Src-H3 acetylation signaling axis integrates macrophage mechanosensation with inflammatory response

Macrophages are mechanosensitive cells that can exquisitely fine-tune their function in response to their microenvironment. While macrophage polarization results in concomitant changes in cell morphology and epigenetic reprogramming, how biophysically-induced signaling cascades contribute to gene re...

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Autores principales: Veerasubramanian, Praveen Krishna, Shao, Hanjuan, Meli, Vijaykumar S., Phan, Tri Andrew Q., Luu, Thuy U., Liu, Wendy F., Downing, Timothy L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8939266/
https://www.ncbi.nlm.nih.gov/pubmed/34753038
http://dx.doi.org/10.1016/j.biomaterials.2021.121236
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author Veerasubramanian, Praveen Krishna
Shao, Hanjuan
Meli, Vijaykumar S.
Phan, Tri Andrew Q.
Luu, Thuy U.
Liu, Wendy F.
Downing, Timothy L.
author_facet Veerasubramanian, Praveen Krishna
Shao, Hanjuan
Meli, Vijaykumar S.
Phan, Tri Andrew Q.
Luu, Thuy U.
Liu, Wendy F.
Downing, Timothy L.
author_sort Veerasubramanian, Praveen Krishna
collection PubMed
description Macrophages are mechanosensitive cells that can exquisitely fine-tune their function in response to their microenvironment. While macrophage polarization results in concomitant changes in cell morphology and epigenetic reprogramming, how biophysically-induced signaling cascades contribute to gene regulatory programs that drive polarization remains unknown. We reveal a cytoskeleton-dependent Src-H3 acetylation (H3Ac) axis responsible for inflammation-associated histone hyperacetylation. Inflammatory stimuli caused increases in traction forces, Src activity and H3Ac marks in macrophages, accompanied by reduced cell elongation and motility. These effects were curtailed following disruption of H3Ac-signaling through either micropattern-induced cell elongation or inhibition of H3Ac readers (BRD proteins) directly. Src activation relieves the suppression of p300 histone acetyltransferase (HAT) activity by PKCδ. Furthermore, while inhibition of Src reduced p300 HAT activity and H3Ac marks globally, local H3Ac levels within the Src promoter were increased, suggesting H3Ac regulates Src levels through feedback. Together, our study reveals an adhesome-to-epigenome regulatory nexus underlying macrophage mechanosensation, where Src modulates H3Ac-associated epigenetic signaling as a means of tuning inflammatory gene activity and macrophage fate decisions in response to microenvironmental cues.
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spelling pubmed-89392662022-03-22 A Src-H3 acetylation signaling axis integrates macrophage mechanosensation with inflammatory response Veerasubramanian, Praveen Krishna Shao, Hanjuan Meli, Vijaykumar S. Phan, Tri Andrew Q. Luu, Thuy U. Liu, Wendy F. Downing, Timothy L. Biomaterials Article Macrophages are mechanosensitive cells that can exquisitely fine-tune their function in response to their microenvironment. While macrophage polarization results in concomitant changes in cell morphology and epigenetic reprogramming, how biophysically-induced signaling cascades contribute to gene regulatory programs that drive polarization remains unknown. We reveal a cytoskeleton-dependent Src-H3 acetylation (H3Ac) axis responsible for inflammation-associated histone hyperacetylation. Inflammatory stimuli caused increases in traction forces, Src activity and H3Ac marks in macrophages, accompanied by reduced cell elongation and motility. These effects were curtailed following disruption of H3Ac-signaling through either micropattern-induced cell elongation or inhibition of H3Ac readers (BRD proteins) directly. Src activation relieves the suppression of p300 histone acetyltransferase (HAT) activity by PKCδ. Furthermore, while inhibition of Src reduced p300 HAT activity and H3Ac marks globally, local H3Ac levels within the Src promoter were increased, suggesting H3Ac regulates Src levels through feedback. Together, our study reveals an adhesome-to-epigenome regulatory nexus underlying macrophage mechanosensation, where Src modulates H3Ac-associated epigenetic signaling as a means of tuning inflammatory gene activity and macrophage fate decisions in response to microenvironmental cues. 2021-12 2021-10-29 /pmc/articles/PMC8939266/ /pubmed/34753038 http://dx.doi.org/10.1016/j.biomaterials.2021.121236 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) ).
spellingShingle Article
Veerasubramanian, Praveen Krishna
Shao, Hanjuan
Meli, Vijaykumar S.
Phan, Tri Andrew Q.
Luu, Thuy U.
Liu, Wendy F.
Downing, Timothy L.
A Src-H3 acetylation signaling axis integrates macrophage mechanosensation with inflammatory response
title A Src-H3 acetylation signaling axis integrates macrophage mechanosensation with inflammatory response
title_full A Src-H3 acetylation signaling axis integrates macrophage mechanosensation with inflammatory response
title_fullStr A Src-H3 acetylation signaling axis integrates macrophage mechanosensation with inflammatory response
title_full_unstemmed A Src-H3 acetylation signaling axis integrates macrophage mechanosensation with inflammatory response
title_short A Src-H3 acetylation signaling axis integrates macrophage mechanosensation with inflammatory response
title_sort src-h3 acetylation signaling axis integrates macrophage mechanosensation with inflammatory response
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8939266/
https://www.ncbi.nlm.nih.gov/pubmed/34753038
http://dx.doi.org/10.1016/j.biomaterials.2021.121236
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