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Functional role of kallikrein 5 and proteinase-activated receptor 2 in eosinophilic esophagitis.
Science Translational Medicine ( IF 17.1 ) Pub Date : 2020-05-27 , DOI: 10.1126/scitranslmed.aaz7773
Nurit P Azouz 1 , Andrea M Klingler 1 , Purnima Pathre 1 , John A Besse 1 , Netali Ben Baruch-Morgenstern 1 , Adina Y Ballaban 1 , Garrett A Osswald 1 , Michael Brusilovsky 1 , Jeff E Habel 1 , Julie M Caldwell 1 , Mario A Ynga-Durand 1, 2 , Pablo J Abonia 1 , Yueh-Chiang Hu 3 , Ting Wen 1 , Marc E Rothenberg 1
Affiliation  

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 SPINK7 mediates its pro-EoE effects via kallikrein 5 (KLK5) and its substrate, protease-activated receptor 2 (PAR2). Overexpression of KLK5 in differentiated esophageal epithelial cells recapitulated the effect of SPINK7 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 SPINK7 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.



中文翻译:

激肽释放酶 5 和蛋白酶激活受体 2 在嗜酸性食管炎中的功能作用。

嗜酸性食管炎 (EoE) 是一种慢性、食物抗原驱动的食管炎性疾病,与屏障功能受损有关。越来越多的证据表明,丝氨酸肽酶抑制剂 kazal 7 型 (SPINK7) 的食管表达缺失是 EoE 发病机制的上游事件。在这里,我们提供证据表明SPINK7的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。KLK5在分化的食管上皮细胞中的过表达概括了SPINK7的作用基因沉默,包括屏障损伤和desmoglein-1表达的丧失。相反,KLK5 缺乏会减弱 EoE 小鼠模型中过敏原诱导的食管蛋白酶活性,改变共生微生物组组成,并减弱嗜酸性粒细胞增多。PAR2的抑制减弱了与SPINK7缺失相关的细胞因子产生在上皮细胞中并减弱体内过敏原诱导的食管嗜酸性粒细胞增多。临床样本证实 EoE 患者食道中 PAR2 表达失调,并且临床批准的药物 α1 抗胰蛋白酶(A1AT,一种蛋白酶抑制剂)的递送抑制了实验性 EoE。这些发现证明了 KLK5 和食道中蛋白酶抑制剂之间平衡的作用,并强调了 EoE 作为一种蛋白酶介导的疾病。我们建议拮抗 KLK5 和/或 PAR2 具有治疗 EoE 的潜力。

更新日期:2020-05-27
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