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

Praveen Krishna Veerasubramanian; Hanjuan Shao; Vijaykumar S Meli; Tri Andrew Q Phan; Thuy U Luu; Wendy F Liu; Timothy L Downing

doi:10.1016/j.biomaterials.2021.121236

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

Biomaterials. 2021 Dec:279:121236. doi: 10.1016/j.biomaterials.2021.121236. Epub 2021 Oct 29.

Authors

Praveen Krishna Veerasubramanian¹, Hanjuan Shao¹, Vijaykumar S Meli¹, Tri Andrew Q Phan¹, Thuy U Luu², Wendy F Liu³, Timothy L Downing⁴

Affiliations

¹ Department of Biomedical Engineering, University of California Irvine, Irvine, CA, USA; UCI Edwards Lifesciences Foundation Cardiovascular Innovation and Research Center (CIRC), University of California Irvine, Irvine, CA, USA.
² UCI Edwards Lifesciences Foundation Cardiovascular Innovation and Research Center (CIRC), University of California Irvine, Irvine, CA, USA; Department of Pharmacological Sciences, University of California Irvine, Irvine, CA, USA.
³ Department of Biomedical Engineering, University of California Irvine, Irvine, CA, USA; UCI Edwards Lifesciences Foundation Cardiovascular Innovation and Research Center (CIRC), University of California Irvine, Irvine, CA, USA; Department of Chemical and Biomolecular Engineering, University of California Irvine, Irvine, CA, USA; Institute for Immunology, University of California Irvine, Irvine, CA, USA; Department of Molecular Biology and Biochemistry, University of California Irvine, Irvine, CA, USA.
⁴ Department of Biomedical Engineering, University of California Irvine, Irvine, CA, USA; UCI Edwards Lifesciences Foundation Cardiovascular Innovation and Research Center (CIRC), University of California Irvine, Irvine, CA, USA; NSF-Simons Center for Multiscale Cell Fate Research, University of California Irvine, Irvine, CA, USA; Department of Microbiology and Molecular Genetics, University of California Irvine, Irvine, CA, USA. Electronic address: tim.downing@uci.edu.

Abstract

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.

Keywords: Biophysical cues; Epigenetic regulation; Inflammation; Macrophages; Src-kinase signaling.

Publication types

Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Acetylation
Histone Acetyltransferases* / metabolism
Histones* / metabolism
Macrophages / metabolism
Signal Transduction

Substances

Histones
Histone Acetyltransferases

Abstract

Publication types

MeSH terms

Substances

Grants and funding