Skip to main content

Lund University Publications

LUND UNIVERSITY LIBRARIES

Suppression of smooth muscle cell inflammation by myocardin-related transcription factors involves inactivation of TANK-binding kinase 1

Bankell, Elisabeth LU ; Liu, Li LU ; van der Horst, Jennifer ; Rippe, Catarina LU ; Jepps, Thomas A ; Nilsson, Bengt-Olof LU orcid and Swärd, Karl LU (2024) In Scientific Reports 14(1).
Abstract

Myocardin-related transcription factors (MRTFs: myocardin/MYOCD, MRTF-A/MRTFA, and MRTF-B/MRTFB) suppress production of pro-inflammatory cytokines and chemokines in human smooth muscle cells (SMCs) through sequestration of RelA in the NF-κB complex, but additional mechanisms are likely involved. The cGAS-STING pathway is activated by double-stranded DNA in the cytosolic compartment and acts through TANK-binding kinase 1 (TBK1) to spark inflammation. The present study tested if MRTFs suppress inflammation also by targeting cGAS-STING signaling. Interrogation of a transcriptomic dataset where myocardin was overexpressed using a panel of 56 cGAS-STING cytokines showed the panel to be repressed. Moreover, MYOCD, MRTFA, and SRF associated... (More)

Myocardin-related transcription factors (MRTFs: myocardin/MYOCD, MRTF-A/MRTFA, and MRTF-B/MRTFB) suppress production of pro-inflammatory cytokines and chemokines in human smooth muscle cells (SMCs) through sequestration of RelA in the NF-κB complex, but additional mechanisms are likely involved. The cGAS-STING pathway is activated by double-stranded DNA in the cytosolic compartment and acts through TANK-binding kinase 1 (TBK1) to spark inflammation. The present study tested if MRTFs suppress inflammation also by targeting cGAS-STING signaling. Interrogation of a transcriptomic dataset where myocardin was overexpressed using a panel of 56 cGAS-STING cytokines showed the panel to be repressed. Moreover, MYOCD, MRTFA, and SRF associated negatively with the panel in human arteries. RT-qPCR in human bronchial SMCs showed that all MRTFs reduced pro-inflammatory cytokines on the panel. MRTFs diminished phosphorylation of TBK1, while STING phosphorylation was marginally affected. The TBK1 inhibitor amlexanox, but not the STING inhibitor H-151, reduced the anti-inflammatory effect of MRTF-A. Co-immunoprecipitation and proximity ligation assays supported binding between MRTF-A and TBK1 in SMCs. MRTFs thus appear to suppress cellular inflammation in part by acting on the kinase TBK1. This may defend SMCs against pro-inflammatory insults in disease.

(Less)
Please use this url to cite or link to this publication:
author
; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Humans, Protein Serine-Threonine Kinases/metabolism, Nuclear Proteins/metabolism, Myocytes, Smooth Muscle/metabolism, Trans-Activators/metabolism, Inflammation/metabolism, Signal Transduction, Cytokines/metabolism, Phosphorylation, Transcription Factors/metabolism, Membrane Proteins/metabolism, Cells, Cultured
in
Scientific Reports
volume
14
issue
1
article number
13321
pages
19 pages
publisher
Nature Publishing Group
external identifiers
  • pmid:38858497
  • scopus:85195476658
ISSN
2045-2322
DOI
10.1038/s41598-024-63901-3
language
English
LU publication?
yes
additional info
© 2024. The Author(s).
id
a35b24ab-34ab-482b-a56b-1f62877f6db7
date added to LUP
2024-06-28 15:37:30
date last changed
2024-06-29 04:02:02
@article{a35b24ab-34ab-482b-a56b-1f62877f6db7,
  abstract     = {{<p>Myocardin-related transcription factors (MRTFs: myocardin/MYOCD, MRTF-A/MRTFA, and MRTF-B/MRTFB) suppress production of pro-inflammatory cytokines and chemokines in human smooth muscle cells (SMCs) through sequestration of RelA in the NF-κB complex, but additional mechanisms are likely involved. The cGAS-STING pathway is activated by double-stranded DNA in the cytosolic compartment and acts through TANK-binding kinase 1 (TBK1) to spark inflammation. The present study tested if MRTFs suppress inflammation also by targeting cGAS-STING signaling. Interrogation of a transcriptomic dataset where myocardin was overexpressed using a panel of 56 cGAS-STING cytokines showed the panel to be repressed. Moreover, MYOCD, MRTFA, and SRF associated negatively with the panel in human arteries. RT-qPCR in human bronchial SMCs showed that all MRTFs reduced pro-inflammatory cytokines on the panel. MRTFs diminished phosphorylation of TBK1, while STING phosphorylation was marginally affected. The TBK1 inhibitor amlexanox, but not the STING inhibitor H-151, reduced the anti-inflammatory effect of MRTF-A. Co-immunoprecipitation and proximity ligation assays supported binding between MRTF-A and TBK1 in SMCs. MRTFs thus appear to suppress cellular inflammation in part by acting on the kinase TBK1. This may defend SMCs against pro-inflammatory insults in disease.</p>}},
  author       = {{Bankell, Elisabeth and Liu, Li and van der Horst, Jennifer and Rippe, Catarina and Jepps, Thomas A and Nilsson, Bengt-Olof and Swärd, Karl}},
  issn         = {{2045-2322}},
  keywords     = {{Humans; Protein Serine-Threonine Kinases/metabolism; Nuclear Proteins/metabolism; Myocytes, Smooth Muscle/metabolism; Trans-Activators/metabolism; Inflammation/metabolism; Signal Transduction; Cytokines/metabolism; Phosphorylation; Transcription Factors/metabolism; Membrane Proteins/metabolism; Cells, Cultured}},
  language     = {{eng}},
  month        = {{06}},
  number       = {{1}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Scientific Reports}},
  title        = {{Suppression of smooth muscle cell inflammation by myocardin-related transcription factors involves inactivation of TANK-binding kinase 1}},
  url          = {{http://dx.doi.org/10.1038/s41598-024-63901-3}},
  doi          = {{10.1038/s41598-024-63901-3}},
  volume       = {{14}},
  year         = {{2024}},
}