Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Nov;36(11):e22609.
doi: 10.1096/fj.202101817RR.

NR4A1 modulates intestinal smooth muscle cell phenotype and dampens inflammation-associated intestinal remodeling

Holly E Szczepanski  1   2 , Kyle L Flannigan  1   2 , Barbara Mainoli  1   2   3 , Laurie Alston  1   2 , Grace M Baruta  1   2 , Joshua W Lee  1   2 , Vivek Krishna Pulakazhi Venu  1   2 , Jane Shearer  2   3   4 , Antoine Dufour  1   2   3   5 , Simon A Hirota  1   2   4   6
Affiliations

NR4A1 modulates intestinal smooth muscle cell phenotype and dampens inflammation-associated intestinal remodeling

Holly E Szczepanski et al. FASEB J. 2022 Nov.

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+/+ and Nr4a1-/- 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+/+ and Nr4a1-/- 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-/- mice exhibited increased abundance of proteins related to cell proliferation, metabolism, and ECM production, whereas Nr4a1+/+ SMCs highly expressed proteins related to the regulation of the actin cytoskeleton and contractile processes. SMCs isolated from Nr4a1-/- mice exhibited increased proliferation and alterations in cellular metabolism, whereas activation of NR4A1 attenuated proliferation. In vivo, Nr4a1-/- 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.

Keywords: Crohn's disease; NR4A1; fibrostenosis; inflammation; smooth muscle.

PubMed Disclaimer

References

REFERENCES

    1. Chen W, Lu C, Hirota C, Iacucci M, Ghosh S, Gui X. Smooth muscle hyperplasia/hypertrophy is the most prominent histological change in Crohn's fibrostenosing bowel strictures: a semiquantitative analysis by using a novel histological grading scheme. J Crohns Colitis. 2017;11(1):92-104. doi:10.1093/ecco-jcc/jjw126
    1. Schoepfer A, Safroneeva E, Vavricka S, Peyrin-Biroulet L, Mottet C. Treatment of fibrostenotic and fistulizing Crohn's disease. Digestion. 2012;86:23-27. doi:10.1159/000341961
    1. Sokol H, Seksik P, Cosnes J. Complications and surgery in the inflammatory bowel diseases biological era. Curr Opin Gastroenterol. 2014;30(4):378-384. doi:10.1097/MOG.0000000000000078
    1. Thia KT, Sandborn WJ, Harmsen WS, Zinsmeister AR, Loftus EV. Risk factors associated with progression to intestinal complications of Crohn's disease in a population-based cohort. Gastroenterology. 2010;139(4):1147-1155. doi:10.1053/j.gastro.2010.06.070
    1. Cosnes J, Nion-Larmurier I, Beaugerie L, Afchain P, Tiret E, Gendre JP. Impact of the increasing use of immunosuppressants in Crohn's disease on the need for intestinal surgery. Gut. 2005;54(2):237-241. doi:10.1136/gut.2004.045294

Publication types

Grants and funding

LinkOut - more resources