The Mesenteric Adipokine SFRP5 Alleviated Intestinal Epithelial Apoptosis Improving Barrier Dysfunction in Crohn's Disease

Overview

Journal iScience

Publisher Cell Press

Date 2025 Jan 6

PMID 39759008

Authors

Xiaofeng Zhang

Lugen Zuo

Xue Song

Wenjing Zhang

Zi Yang

Zhiyuan Wang

Yibing Guo

Sitang Ge

Lian Wang

Yueyue Wang

Zhijun Geng

Jing Li

Jianguo Hu

Affiliations

Soon will be listed here.

Abstract

The hypertrophic mesenteric adipose tissue (htMAT) of Crohn disease (CD) participates in inflammation through the expression of adipokines, but the exact mechanism of this action in the intestine is unknown. Here, we analyzed the expression of secreted frizzled-related protein 5 (SFRP5), an adipokine with cytoprotective effects, in htMAT and its role in CD. The results of this study revealed that the level of SFPR5 increased in the diseased MAT (htMAT) of CD patients and aggregated among intestinal epithelial cells in the diseased intestine and that it could ameliorate intestinal barrier dysfunction in tumor necrosis factor alpha (TNF-α)-stimulated colonic organoids and 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced mice at least in part through the inhibition of Wnt5a-mediated apoptosis in epithelial cells. This study elucidates possible mechanisms by which mesenteric adipokines influence the progression of enteritis and provides a new theoretical basis for the treatment of CD via the mesenteric pathway.

References

Huang Q, Yang Y, Zhu Y, Chen Q, Zhao T, Xiao Z . Oral Metal-Free Melanin Nanozymes for Natural and Durable Targeted Treatment of Inflammatory Bowel Disease (IBD). Small. 2023; 19(19):e2207350. DOI: 10.1002/smll.202207350. View

Zuo L, Ge S, Ge Y, Li J, Zhu B, Zhang Z . The Adipokine Metrnl Ameliorates Chronic Colitis in Il-10-/- Mice by Attenuating Mesenteric Adipose Tissue Lesions During Spontaneous Colitis. J Crohns Colitis. 2019; 13(7):931-941. DOI: 10.1093/ecco-jcc/jjz001. View

Payne G, Borbouse L, Kumar S, Neeb Z, Alloosh M, Sturek M . Epicardial perivascular adipose-derived leptin exacerbates coronary endothelial dysfunction in metabolic syndrome via a protein kinase C-beta pathway. Arterioscler Thromb Vasc Biol. 2010; 30(9):1711-7. PMC: 2924445. DOI: 10.1161/ATVBAHA.110.210070. View

Mao R, Kurada S, Gordon I, Baker M, Gandhi N, McDonald C . The Mesenteric Fat and Intestinal Muscle Interface: Creeping Fat Influencing Stricture Formation in Crohn's Disease. Inflamm Bowel Dis. 2018; 25(3):421-426. DOI: 10.1093/ibd/izy331. View

Koelink P, Wildenberg M, Stitt L, Feagan B, Koldijk M, van t Wout A . Development of Reliable, Valid and Responsive Scoring Systems for Endoscopy and Histology in Animal Models for Inflammatory Bowel Disease. J Crohns Colitis. 2018; 12(7):794-803. PMC: 6022651. DOI: 10.1093/ecco-jcc/jjy035. View

Zhang X, Zuo L, Geng Z, Song X, Li J, Ge S . Vindoline ameliorates intestinal barrier damage in Crohn's disease mice through MAPK signaling pathway. FASEB J. 2022; 36(11):e22589. DOI: 10.1096/fj.202200234RR. View

Wen H, Zhang X, Li Q, Huang J, Liu G, Zhao J . Ruscogenins Improve CD-Like Enteritis by Inhibiting Apoptosis of Intestinal Epithelial Cells and Activating Nrf2/NQO1 Pathway. Oxid Med Cell Longev. 2022; 2022:4877275. PMC: 8930266. DOI: 10.1155/2022/4877275. View

Ding N, Zheng C . Secreted frizzled-related protein 5 promotes angiogenesis of human umbilical vein endothelial cells and alleviates myocardial injury in diabetic mice with myocardial infarction by inhibiting Wnt5a/JNK signaling. Bioengineered. 2022; 13(5):11656-11667. PMC: 9275896. DOI: 10.1080/21655979.2022.2070964. View

Nosalski R, Guzik T . Perivascular adipose tissue inflammation in vascular disease. Br J Pharmacol. 2017; 174(20):3496-3513. PMC: 5610164. DOI: 10.1111/bph.13705. View

10.

Spencer D, Veldman G, Banerjee S, Willis J, Levine A . Distinct inflammatory mechanisms mediate early versus late colitis in mice. Gastroenterology. 2002; 122(1):94-105. DOI: 10.1053/gast.2002.30308. View

11.

Zhou W, Ye C, Li L, Liu L, Wang F, Yu L . Adipocyte-derived SFRP5 inhibits breast cancer cells migration and invasion through Wnt and epithelial-mesenchymal transition signaling pathways. Chin J Cancer Res. 2020; 32(3):347-360. PMC: 7369183. DOI: 10.21147/j.issn.1000-9604.2020.03.06. View

12.

Meijer B, Giugliano F, Baan B, van der Meer J, Meisner S, van Roest M . ATF2 and ATF7 Are Critical Mediators of Intestinal Epithelial Repair. Cell Mol Gastroenterol Hepatol. 2020; 10(1):23-42. PMC: 7210476. DOI: 10.1016/j.jcmgh.2020.01.005. View

13.

Tong S, Ji Q, Du Y, Zhu X, Zhu C, Zhou Y . Sfrp5/Wnt Pathway: A Protective Regulatory System in Atherosclerotic Cardiovascular Disease. J Interferon Cytokine Res. 2019; 39(8):472-482. PMC: 6660834. DOI: 10.1089/jir.2018.0154. View

14.

Ouchi N, Higuchi A, Ohashi K, Oshima Y, Gokce N, Shibata R . Sfrp5 is an anti-inflammatory adipokine that modulates metabolic dysfunction in obesity. Science. 2010; 329(5990):454-7. PMC: 3132938. DOI: 10.1126/science.1188280. View

15.

Bruewer M, Luegering A, Kucharzik T, Parkos C, Madara J, Hopkins A . Proinflammatory cytokines disrupt epithelial barrier function by apoptosis-independent mechanisms. J Immunol. 2003; 171(11):6164-72. DOI: 10.4049/jimmunol.171.11.6164. View

16.

Blaszczak A, Jalilvand A, Hsueh W . Adipocytes, Innate Immunity and Obesity: A Mini-Review. Front Immunol. 2021; 12:650768. PMC: 8264354. DOI: 10.3389/fimmu.2021.650768. View

17.

Sakurai T, Katsuno T, Saito K, Yoshihama S, Nakagawa T, Koseki H . Mesenteric findings of CT enterography are well correlated with the endoscopic severity of Crohn's disease. Eur J Radiol. 2017; 89:242-248. DOI: 10.1016/j.ejrad.2016.10.022. View

18.

Gunther C, Neumann H, Neurath M, Becker C . Apoptosis, necrosis and necroptosis: cell death regulation in the intestinal epithelium. Gut. 2012; 62(7):1062-71. DOI: 10.1136/gutjnl-2011-301364. View

19.

Song X, Huang Q, Yang Y, Ma L, Liu W, Ou C . Efficient Therapy of Inflammatory Bowel Disease (IBD) with Highly Specific and Durable Targeted Ta C Modified with Chondroitin Sulfate (TACS). Adv Mater. 2023; 35(36):e2301585. DOI: 10.1002/adma.202301585. View

20.

Patterson L, Allen J, Posey I, Shaw J, Costa-Pinheiro P, Walker S . Glucosylceramide production maintains colon integrity in response to Bacteroides fragilis toxin-induced colon epithelial cell signaling. FASEB J. 2020; 34(12):15922-15945. PMC: 8140605. DOI: 10.1096/fj.202001669R. View