| Popis: |
Eosinophilic esophagitis (EoE) is an allergic inflammatory disease of the esophagus that is caused by both genetic and environmental factors. Herein, we investigated leucine-rich repeat–containing protein 31 (LRRC31), a protein that regulates esophageal epithelial function, and LRRC32, which was genetically associated with EoE and allergic diseases. We show that LRRC31 increased in the esophagus of patients with active EoE. LRRC31 mRNA and protein were increased in differentiated, IL-13–treated esophageal epithelial (EPC2) cells grown at the air liquid interface (ALI). LRRC31 overexpressing EPC2 cells had increased epithelial barrier function and RNA sequencing analysis identified 38 dysregulated genes, including 5 kallikrein (KLK) proteases. Indeed, KLK protein and proteolytic activity levels were decreased in LRRC31-overexpressing EPC2 cells. KLK expression was similarly dysregulated in the esophagus of EoE patients and in IL-13–treated esophageal epithelial cells. Thus, we propose that LRRC31 is induced by IL-13 and modulates epithelial barrier function, potentially by regulating KLK expression. LRRC32 is an immune-related protein that is similar in structure to LRRC31. We identified rs2155219, a single nucleotide polymorphism (SNP) associated with EoE that was an enhancer of gene transcription. The minor allele at rs2155219 decreased the risk of developing EoE and increased esophageal expression of LRRC32 mRNA in EoE patients. In addition, IL-13 induced LRRC32 mRNA expression in EPC2 cells. We propose that LRRC32 is important for disease pathogenesis and decreased esophageal expression may correlate with lower risk of EoE. In conclusion, LRRC31 and LRRC32 are both involved in two independent pathways contributing to EoE pathogenesis. A further understanding of their roles in EoE and allergic diseases may facilitate the development of alternative therapeutics to improve the quality of life for patients. |
