Control of Intestinal Epithelial Permeability by Lysophosphatidic Acid Receptor 5
| Autor: | Mo Wang, C. Chris Yun, Yiran Han, Lei Dong, Peijian He |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Male Lipopolysaccharide RC799-869 RT-PCR reverse transcriptase polymerase chain reaction IEC intestinal epithelial cell Cell membrane chemistry.chemical_compound Transactivation Mice 0302 clinical medicine LPA5 FD-4 fluorescein isothiocyanate-labeled 4 kDa dextran Lysophosphatidic acid Intestinal Mucosa Receptors Lysophosphatidic Acid Receptor Original Research ATX autotaxin IBD inflammatory bowel disease Dextran Sulfate Gastroenterology Diseases of the digestive system. Gastroenterology GI gastrointestinal Colitis Cell biology LPA medicine.anatomical_structure TJ tight junction shRNA short hairpin RNA LPS lipopolysaccharide 030211 gastroenterology & hepatology Signal transduction JAMs junctional adhesion molecules Rac1 LPA lysophosphatidic acid LPA5 LPA receptor 5 Barrier PBS phosphate-buffered saline RAC1 ROCK RhoA-associated kinase Permeability TER transepithelial electrical resistance Cell Line GEF guanine nucleotide exchange factor 03 medical and health sciences Stat signal transducers and activators of transcription DSS dextran sulfate sodium medicine Animals Humans IF immunofluorescence GPCR G protein-coupled receptor Intestinal permeability Hepatology Stat3 NHE3 Na+/H+ exchanger 3 medicine.disease AJ adherens junction EGFR epidermal growth factor receptor Disease Models Animal 030104 developmental biology chemistry Caco-2 Cells Lysophospholipids SD standard deviation |
| Zdroj: | Cellular and Molecular Gastroenterology and Hepatology Cellular and Molecular Gastroenterology and Hepatology, Vol 12, Iss 3, Pp 1073-1092 (2021) |
| ISSN: | 2352-345X |
| Popis: | 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. Graphical abstract |
| Databáze: | OpenAIRE |
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