Control of Intestinal Epithelial Permeability by Lysophosphatidic Acid Receptor 5

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 (LPA(5)) is highly expressed in intestinal epithelial cells, but its role in the intestine is not well-known. Here we determined the role of LPA(5) in regulation of intestinal epithelial barrier. METHODS: Epithelial barrier integrity was determined in mice with intestinal epithelial cell (IEC)-specific LPA(5) deletion, Lpar5(ΔIEC). 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 LPA(5)-mediated signaling pathways that regulate epithelial barrier. RESULTS: We observed increased epithelial permeability in Lpar5(ΔIEC) mice with reduced claudin-4 expression. Oral administration of LPA decreased intestinal permeability in wild-type mice, but the effect was greatly mitigated in Lpar5(ΔIEC) mice. Serum lipopolysaccharide level and bacterial loads in the intestine and liver were elevated in Lpar5(ΔIEC) mice. Lpar5(ΔIEC) mice developed more severe colitis induced with DSS. LPA(5) 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 LPA(5) as a regulator of the intestinal barrier. LPA(5) promotes claudin-4 expression in IECs through activation of Rac1 and Stat3.