title: LRRC31 is induced by IL-13 and regulates kallikrein expression and barrier function in the esophageal epithelium.
abstract: Eosinophilic esophagitis (EoE) is an allergic inflammatory disease of the esophagus featuring increased esophageal interleukin-13 (IL-13) levels and impaired barrier function. Herein, we investigated leucine-rich repeat-containing protein 31 (LRRC31) in human EoE esophageal tissue and IL-13-treated esophageal epithelial cells. LRRC31 had basal mRNA expression in colonic and airway mucosal epithelium. Esophageal LRRC31 mRNA and protein increased in active EoE and strongly correlated with esophageal eosinophilia and IL13 and CCL26 (chemokine (C-C motif) ligand 26) mRNA expression. IL-13 treatment increased LRRC31 mRNA and protein in air-liquid interface-differentiated esophageal epithelial cells (EPC2s). At baseline, differentiated LRRC31-overexpressing EPC2s had increased barrier function (1.9-fold increase in transepithelial electrical resistance (P<0.05) and 2.8-fold decrease in paracellular flux (P<0.05)). RNA sequencing analysis of differentiated LRRC31-overexpressing EPC2s identified 38 dysregulated genes (P<0.05), including five kallikrein (KLK) serine proteases. Notably, differentiated LRRC31-overexpressing EPC2s had decreased KLK expression and activity, whereas IL-13-treated, differentiated LRRC31 gene-silenced EPC2s had increased KLK expression and suprabasal epithelial detachment. We identified similarly dysregulated KLK expression in the esophagus of patients with active EoE and in IL-13-treated esophageal epithelial cells. We propose that LRRC31 is induced by IL-13 and modulates epithelial barrier function, potentially through KLK regulation.
authors.affiliation: Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: D'Mello
authors.affiliation: Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Caldwell
authors.affiliation: Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: N P
authors.initials: NP
authors.lastname: Azouz
authors.affiliation: Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: T
authors.initials: T
authors.lastname: Wen
authors.affiliation: Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Sherrill
authors.affiliation: Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: S P
authors.initials: SP
authors.lastname: Hogan
authors.affiliation: Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: M E
authors.initials: ME
authors.lastname: Rothenberg
mesh_terms: D000328:Adult; D001692:Biological Transport; D002454:Cell Differentiation; D002460:Cell Line; D003911:Dextrans / Q000493:pharmacokinetics; D017097:Electric Impedance; D057765:Eosinophilic Esophagitis / Q000276:immunology*; D004848:Epithelium / Q000378:metabolism* / Q000473:pathology; D004947:Esophagus / Q000276:immunology* / Q000473:pathology; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D005786:Gene Expression Regulation; D006801:Humans; D018793:Interleukin-13 / Q000235:genetics / Q000378:metabolism*; D007610:Kallikreins / Q000235:genetics / Q000378:metabolism*; D000090263:Leucine-Rich Repeat Proteins; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: D003911:Dextrans; D018793:Interleukin-13; C000624426:LRRC31 protein, human; D000090263:Leucine-Rich Repeat Proteins; D009687:Nuclear Proteins; D011506:Proteins; D034741:RNA, Small Interfering; C015219:fluorescein isothiocyanate dextran; D007610:Kallikreins; D016650:Fluorescein-5-isothiocyanate