Epithelial Interleukin-1 Receptor-Like-1 Activation Is Contingent on Interleukin-33 Isoforms and Asthma-Related Receptor Variation.

IF 6.3 2区医学 Q1 ALLERGY Clinical and Experimental Allergy Pub Date : 2024-09-20 DOI:10.1111/cea.14562

Michael A Portelli, Maria E Ketelaar, Stewart Bates, Eszter Csomor, Dominick Shaw, Jonas Emsley, Christopher Brightling, Ian Hall, Karen Affleck, Matthew Edwards, Martijn C Nawijn, Gerard H Koppelman, Antoon J Van Oosterhout, Ian Sayers

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Abstract

Introduction: The interleukin-33/interleukin-1 receptor-like-1 (IL-33/IL1RL1) signalling pathway is implicated in asthma pathogenesis, with IL1RL1 nonsynonymous genetic polymorphisms associated with disease risk. We aimed to determine these variants' effect on IL1RL1 signalling induced by different IL33 isoforms thought to be elevated in the asthmatic airway.

Method: In a project funded by GSK plc, which has developed an IL-33 receptor inhibitor for asthma treatment, human embryonic kidney 293 (HEK293) cells expressing secreted embryonic alkaline phosphatase (SEAP) driven by a nuclear factor kappa-beta (NF-κB) promoter, were transiently transfected with IL1RL1, containing one of four extracellular and Toll/interleukin 1 receptor (TIR) domain haplotypes. Cells were stimulated with seven different splice and proteolytic-generated IL-33 isoforms (0.001-50 ng/mL) for 24 h. Supernatant SEAP activity and interleukin-8 (IL-8) levels were determined. Primary human bronchial epithelial cells (HBECs) representing different genotype carriers were stimulated with IL-33_112-270 (50 ng/mL) and induced IL-8 mRNA expression measured.

Results: HEK293 cells carrying both asthma extracellular and TIR domain IL1RL1 risk haplotypes presented maximal IL33-driven signalling, with minimal signalling after IL-33 activation in other protective haplotypes. All IL-33 isoforms activated IL1RL1 but with differing magnitudes. Proteolytically cleaved IL33_95-270 and IL33_106-270 had the greatest effect and the IL33_113-270, and Exon 3,4 deletion isoform exhibited the lowest. The effect of extracellular and TIR domain genetic variants on receptor signalling was replicated in primary HBECs. Maximal IL1RL1 signalling was observed in cells carrying both extracellular and TIR signalling domain risk haplotypes.

Conclusions: Overall, our study suggests asthma patients carrying the extracellular and TIR domain risk haplotype and have a lung microenvironment that promotes elevated levels of cleaved IL33, particularly where IL33_95-270 and IL33_106-270 may be more amenable to IL33/IL1RL1 targeting.

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上皮细胞白细胞介素-1 受体样-1 激活取决于白细胞介素-33 同工型和哮喘相关受体变异。

导言：白细胞介素-33/白细胞介素-1受体样-1（IL-33/IL1RL1）信号通路与哮喘发病机制有关，IL1RL1非同义遗传多态性与疾病风险相关。我们旨在确定这些变异对哮喘气道中被认为升高的不同 IL33 异构体所诱导的 IL1RL1 信号传导的影响：在一个由葛兰素史克公司（GSK plc）资助的项目中（该公司已开发出一种用于治疗哮喘的IL-33受体抑制剂），表达由核因子卡巴-β（NF-κB）启动子驱动的分泌型胚胎碱性磷酸酶（SEAP）的人胚胎肾脏293（HEK293）细胞被瞬时转染了含有四种细胞外和Toll/白介素1受体（TIR）结构域单倍型之一的IL1RL1。用七种不同的剪接和蛋白水解产生的 IL-33 异构体（0.001-50 毫微克/毫升）刺激细胞 24 小时，测定上清液 SEAP 活性和白细胞介素-8（IL-8）水平。用 IL-33112-270（50 ng/mL）刺激代表不同基因型携带者的原代人支气管上皮细胞（HBECs），并测定诱导的 IL-8 mRNA 表达：结果：携带哮喘细胞外结构域和TIR结构域IL1RL1风险单倍型的HEK293细胞呈现最大的IL33驱动信号，而其他保护性单倍型细胞在IL-33激活后信号最小。所有 IL-33 异构体都能激活 IL1RL1，但激活程度不同。蛋白水解IL3395-270和IL33106-270的作用最大，而IL33113-270和外显子3、4缺失异构体的作用最小。细胞外和 TIR 结构域基因变体对受体信号的影响在原代 HBECs 中得到了复制。在携带细胞外和TIR信号结构域风险单倍型的细胞中观察到了最大的IL1RL1信号传导：总之，我们的研究表明，携带细胞外和 TIR 信号结构域风险单倍型的哮喘患者的肺部微环境会促进裂解 IL33 水平的升高，尤其是 IL3395-270 和 IL33106-270 可能更适合 IL33/IL1RL1 靶向。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Clinical and Experimental Allergy 医学-过敏

CiteScore

10.40

自引率

9.80%

发文量

189

审稿时长

3-8 weeks

期刊介绍： Clinical & Experimental Allergy strikes an excellent balance between clinical and scientific articles and carries regular reviews and editorials written by leading authorities in their field. In response to the increasing number of quality submissions, since 1996 the journals size has increased by over 30%. Clinical & Experimental Allergy is essential reading for allergy practitioners and research scientists with an interest in allergic diseases and mechanisms. Truly international in appeal, Clinical & Experimental Allergy publishes clinical and experimental observations in disease in all fields of medicine in which allergic hypersensitivity plays a part.