Suppression of smooth muscle cell inflammation by myocardin-related transcription factors involves inactivation of TANK-binding kinase 1
(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)
- author
- Bankell, Elisabeth
LU
; Liu, Li
LU
; van der Horst, Jennifer
; Rippe, Catarina
LU
; Jepps, Thomas A
; Nilsson, Bengt-Olof
LU
and Swärd, Karl LU
- organization
- publishing date
- 2024-06-10
- 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}}, }