Azouz Nurit P, Klingler Andrea M, Pathre Purnima, Besse John A, Baruch-Morgenstern Netali Ben, Ballaban Adina Y, Osswald Garrett A, Brusilovsky Michael, Habel Jeff E, Caldwell Julie M, Ynga-Durand Mario A, Abonia Pablo J, Hu Yueh-Chiang, Wen Ting, Rothenberg Marc E
Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229-3026, USA.
Laboratorio de Inmunidad de Mucosas, Sección de Investigación y Posgrado, Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico City, Mexico.
Sci Transl Med. 2020 May 27;12(545). doi: 10.1126/scitranslmed.aaz7773.
Eosinophilic esophagitis (EoE) is a chronic, food antigen-driven, inflammatory disease of the esophagus and is associated with impaired barrier function. Evidence is emerging that loss of esophageal expression of the serine peptidase inhibitor, kazal type 7 (SPINK7), is an upstream event in EoE pathogenesis. Here, we provide evidence that loss of mediates its pro-EoE effects via kallikrein 5 (KLK5) and its substrate, protease-activated receptor 2 (PAR2). Overexpression of in differentiated esophageal epithelial cells recapitulated the effect of gene silencing, including barrier impairment and loss of desmoglein-1 expression. Conversely, KLK5 deficiency attenuated allergen-induced esophageal protease activity, modified commensal microbiome composition, and attenuated eosinophilia in a murine model of EoE. Inhibition of PAR2 blunted the cytokine production associated with loss of in epithelial cells and attenuated the allergen-induced esophageal eosinophilia in vivo. Clinical samples substantiated dysregulated PAR2 expression in the esophagus of patients with EoE, and delivery of the clinically approved drug α1 antitrypsin (A1AT, a protease inhibitor) inhibited experimental EoE. These findings demonstrate a role for the balance between KLK5 and protease inhibitors in the esophagus and highlight EoE as a protease-mediated disease. We suggest that antagonizing KLK5 and/or PAR2 has potential to be therapeutic for EoE.
嗜酸性食管炎（EoE）是一种慢性的、由食物抗原驱动的食管炎症性疾病，与屏障功能受损有关。越来越多的证据表明，丝氨酸蛋白酶抑制剂卡扎尔7型（SPINK7）在食管中的表达缺失是EoE发病机制中的一个上游事件。在此，我们提供证据表明，其缺失通过激肽释放酶5（KLK5）及其底物蛋白酶激活受体2（PAR2）介导其促EoE作用。在分化的食管上皮细胞中过表达可重现基因沉默的效果，包括屏障损伤和桥粒芯糖蛋白-1表达缺失。相反，在EoE小鼠模型中，KLK5缺陷减弱了变应原诱导的食管蛋白酶活性，改变了共生微生物群组成，并减轻了嗜酸性粒细胞增多。抑制PAR2可减弱与上皮细胞中缺失相关的细胞因子产生，并在体内减轻变应原诱导的食管嗜酸性粒细胞增多。临床样本证实EoE患者食管中PAR2表达失调，而临床批准的药物α1抗胰蛋白酶（A1AT，一种蛋白酶抑制剂）的给药可抑制实验性EoE。这些发现证明了KLK5与蛋白酶抑制剂之间的平衡在食管中的作用，并突出了EoE作为一种蛋白酶介导的疾病。我们认为，拮抗KLK5和/或PAR2可能对EoE具有治疗潜力。
