Control of Intestinal Epithelial Permeability by Lysophosphatidic Acid Receptor 5

• Type of Material: Article
• Authors: Mo Wang, Emory University; Peijian He, Emory University; Yiran Han, Emory University; Lei Dong, The Second Affiliated Hospital, Xi’an Jiaotong University; Changhyon Yun, Emory University
• Language: English
• Date: 2021-07-31
• Publisher: ELSEVIER INC
• Publication Version: Final Published Version
• Copyright Statement: © 2021 The Authors
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.jcmgh.2021.05.003
• Title of Journal or Parent Work: CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
• Volume: 12
• Issue: 3
• Start Page: 1073
• End Page: 1092
• Grant/Funding Information: Confocal microscopic analyses were supported in part by the Integrated Cellular Imaging Shared Resources of Winship Cancer Institute of Emory University and NIH/NCI under award P30CA138292.; Supported by grants from the National Institutes of Health (R01DK116799) and the Veterans Administration Merit Award (I01BX004459). MW was supported by the State Scholarship Fund of the China Scholarship Council.
• Keywords: BARRIER FUNCTION; Barrier; NA+/H+ EXCHANGER 3; RAC1; LPA5; Stat3; EXPRESSION; Rac1; Gastroenterology & Hepatology; CELLS; SUBCELLULAR-LOCALIZATION; RHO KINASE; STAT3; ACTIVATION; Science & Technology; LPA; Life Sciences & Biomedicine; PHOSPHORYLATION
• Research Categories: Health Sciences, Oncology

Abstract

Background & Aims: Epithelial cells form a monolayer at mucosal surface that functions as a highly selective barrier. Lysophosphatidic acid (LPA) is a bioactive lipid that elicits a broad range of biological effects via cognate G protein-coupled receptors. LPA receptor 5 (LPA5) is highly expressed in intestinal epithelial cells, but its role in the intestine is not well-known. Here we determined the role of LPA5 in regulation of intestinal epithelial barrier. Methods: Epithelial barrier integrity was determined in mice with intestinal epithelial cell (IEC)-specific LPA5 deletion, Lpar5ΔIEC. LPA was orally administered to mice, and intestinal permeability was measured. Dextran sulfate sodium (DSS) was used to induce colitis. Human colonic epithelial cell lines were used to determine the LPA5-mediated signaling pathways that regulate epithelial barrier. Results: We observed increased epithelial permeability in Lpar5ΔIEC mice with reduced claudin-4 expression. Oral administration of LPA decreased intestinal permeability in wild-type mice, but the effect was greatly mitigated in Lpar5ΔIEC mice. Serum lipopolysaccharide level and bacterial loads in the intestine and liver were elevated in Lpar5ΔIEC mice. Lpar5ΔIEC mice developed more severe colitis induced with DSS. LPA5 transcriptionally regulated claudin-4, and this regulation was dependent on transactivation of the epidermal growth factor receptor, which induced localization of Rac1 at the cell membrane. LPA induced the translocation of Stat3 to the cell membrane and promoted the interaction between Rac1 and Stat3. Inhibition of Stat3 ablated LPA-mediated regulation of claudin-4. Conclusions: This study identifies LPA5 as a regulator of the intestinal barrier. LPA5 promotes claudin-4 expression in IECs through activation of Rac1 and Stat3.