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NR4A1 modulates intestinal smooth muscle cell phenotype and dampens inflammation-associated intestinal remodeling.
- Source :
-
FASEB journal : official publication of the Federation of American Societies for Experimental Biology [FASEB J] 2022 Nov; Vol. 36 (11), pp. e22609. - Publication Year :
- 2022
-
Abstract
- Stricture formation is a common complication of Crohn's disease (CD), driven by enhanced deposition of extracellular matrix (ECM) and expansion of the intestinal smooth muscle layers. Nuclear receptor subfamily 4 group A member 1 (NR4A1) is an orphan nuclear receptor that exhibits anti-proliferative effects in smooth muscle cells (SMCs). We hypothesized that NR4A1 regulates intestinal SMC proliferation and muscle thickening in the context of inflammation. Intestinal SMCs isolated from Nr4a1 <superscript>+/+</superscript> and Nr4a1 <superscript>-/-</superscript> littermates were subjected to shotgun proteomic analysis, proliferation, and bioenergetic assays. Proliferation was assessed in the presence and absence of NR4A1 agonists, cytosporone-B (Csn-B) and 6-mercaptopurine (6-MP). In vivo, we compared colonic smooth muscle thickening in Nr4a1 <superscript>+/+</superscript> and Nr4a1 <superscript>-/-</superscript> mice using the chronic dextran sulfate sodium (DSS) model of colitis. Second, SAMP1/YitFc mice (a model of spontaneous ileitis) were treated with Csn-B and small intestinal smooth muscle thickening was assessed. SMCs isolated from Nr4a1 <superscript>-/-</superscript> mice exhibited increased abundance of proteins related to cell proliferation, metabolism, and ECM production, whereas Nr4a1 <superscript>+/+</superscript> SMCs highly expressed proteins related to the regulation of the actin cytoskeleton and contractile processes. SMCs isolated from Nr4a1 <superscript>-/-</superscript> mice exhibited increased proliferation and alterations in cellular metabolism, whereas activation of NR4A1 attenuated proliferation. In vivo, Nr4a1 <superscript>-/-</superscript> mice exhibited increased colonic smooth muscle thickness following repeated cycles of DSS. Activating NR4A1 with Csn-B, in the context of established inflammation, reduced ileal smooth muscle thickening in SAMP1/YitFc mice. Targeting NR4A1 may provide a novel approach to regulate intestinal SMC phenotype, limiting excessive proliferation that contributes to stricture development in CD.<br /> (© 2022 Federation of American Societies for Experimental Biology.)
- Subjects :
- Animals
Cells, Cultured
Constriction, Pathologic complications
Constriction, Pathologic metabolism
Dextran Sulfate
Inflammation metabolism
Mice
Muscle, Smooth
Myocytes, Smooth Muscle metabolism
Nuclear Receptor Subfamily 4, Group A, Member 1 genetics
Nuclear Receptor Subfamily 4, Group A, Member 1 metabolism
Orphan Nuclear Receptors metabolism
Phenotype
Phenylacetates
Proteomics
Crohn Disease metabolism
Mercaptopurine metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1530-6860
- Volume :
- 36
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- FASEB journal : official publication of the Federation of American Societies for Experimental Biology
- Publication Type :
- Academic Journal
- Accession number :
- 36250380
- Full Text :
- https://doi.org/10.1096/fj.202101817RR