IL-33/IL-1RL1通路在哮喘中的关键作用：从发病机制到治疗干预
2021/04/23
摘要
白细胞介素-33（IL-33）是IL-1家族的成员，其同源受体白细胞介素-1受体样蛋白-1（IL-1RL1或ST2）是儿童哮喘的易感基因。作为对细胞损伤的反应，IL-33作为一种“警报蛋白”从屏障组织中释放出来，以激活固有免疫反应。IL-33通过其受体IL-1RL1在一些免疫和结构细胞中诱导信号传导驱动2型应答，从而导致2型细胞因子和趋化因子的产生。IL-1RL1基因转录本编码通过选择性剪接产生不同的亚型。其可溶性亚型IL-1RL1-a或sST2通过隔离IL-33发挥诱饵受体的作用，从而抑制IL-1RL1-b/IL-33信号。因此，IL-33及其受体IL-1RL1被认为是哮喘药物干预的生物标志物或靶点。本文综述了IL-33/IL-1RL1通路在哮喘发病机制中的遗传学和生物学意义。本文将讨论靶向细胞因子或其受体的潜力和复杂性，遗传学或生物标记物如何为哮喘靶向这一途径的精准医学提供信息，以及靶向IL-33或其受体的治疗药物在哮喘治疗中应用前景中的可能定位。
The central role of IL-33/IL-1RL1 pathway in asthma: From pathogenesis to intervention.
A K Saikumar Jayalatha, L Hesse, M E Ketelaar, G H Koppelman, M C Nawijn.
Abstract
Interleukin-33 (IL-33), a member of the IL-1 family, and its cognate receptor, Interleukin-1 receptor like-1 (IL-1RL1 or ST2), are susceptibility genes for childhood asthma. In response to cellular damage, IL-33 is released from barrier tissues as an 'alarmin' to activate the innate immune response. IL-33 drives type 2 responses by inducing signalling through its receptor IL-1RL1 in several immune and structural cells, thereby leading to type 2 cytokine and chemokine production. IL-1RL1 gene transcript encodes different isoforms generated through alternative splicing. Its soluble isoform, IL-1RL1-a or sST2, acts as a decoy receptor by sequestering IL-33, thereby inhibiting IL1RL1-b/IL-33 signalling. IL-33 and its receptor IL-1RL1 are therefore considered as putative biomarkers or targets for pharmacological intervention in asthma. This review will provide an overview of the genetics and biology of the IL-33/IL-1RL1 pathway in the context of asthma pathogenesis. It will discuss the potential and complexities of targeting the cytokine or its receptor, how genetics or biomarkers may inform precision medicine for asthma targeting this pathway, and the possible positioning of therapeutics targeting IL-33 or its receptor in the expanding landscape of novel biologicals applied in asthma management.
白细胞介素-33（IL-33）是IL-1家族的成员，其同源受体白细胞介素-1受体样蛋白-1（IL-1RL1或ST2）是儿童哮喘的易感基因。作为对细胞损伤的反应，IL-33作为一种“警报蛋白”从屏障组织中释放出来，以激活固有免疫反应。IL-33通过其受体IL-1RL1在一些免疫和结构细胞中诱导信号传导驱动2型应答，从而导致2型细胞因子和趋化因子的产生。IL-1RL1基因转录本编码通过选择性剪接产生不同的亚型。其可溶性亚型IL-1RL1-a或sST2通过隔离IL-33发挥诱饵受体的作用，从而抑制IL-1RL1-b/IL-33信号。因此，IL-33及其受体IL-1RL1被认为是哮喘药物干预的生物标志物或靶点。本文综述了IL-33/IL-1RL1通路在哮喘发病机制中的遗传学和生物学意义。本文将讨论靶向细胞因子或其受体的潜力和复杂性，遗传学或生物标记物如何为哮喘靶向这一途径的精准医学提供信息，以及靶向IL-33或其受体的治疗药物在哮喘治疗中应用前景中的可能定位。
(中日友好医院呼吸与危重症医学科 顾宪民 摘译 林江涛 审校)
(Pharmacol Ther. 2021 Apr 2;107847.doi: 10.1016/j.pharmthera.2021.107847.)
(Pharmacol Ther. 2021 Apr 2;107847.doi: 10.1016/j.pharmthera.2021.107847.)
The central role of IL-33/IL-1RL1 pathway in asthma: From pathogenesis to intervention.
A K Saikumar Jayalatha, L Hesse, M E Ketelaar, G H Koppelman, M C Nawijn.
Abstract
Interleukin-33 (IL-33), a member of the IL-1 family, and its cognate receptor, Interleukin-1 receptor like-1 (IL-1RL1 or ST2), are susceptibility genes for childhood asthma. In response to cellular damage, IL-33 is released from barrier tissues as an 'alarmin' to activate the innate immune response. IL-33 drives type 2 responses by inducing signalling through its receptor IL-1RL1 in several immune and structural cells, thereby leading to type 2 cytokine and chemokine production. IL-1RL1 gene transcript encodes different isoforms generated through alternative splicing. Its soluble isoform, IL-1RL1-a or sST2, acts as a decoy receptor by sequestering IL-33, thereby inhibiting IL1RL1-b/IL-33 signalling. IL-33 and its receptor IL-1RL1 are therefore considered as putative biomarkers or targets for pharmacological intervention in asthma. This review will provide an overview of the genetics and biology of the IL-33/IL-1RL1 pathway in the context of asthma pathogenesis. It will discuss the potential and complexities of targeting the cytokine or its receptor, how genetics or biomarkers may inform precision medicine for asthma targeting this pathway, and the possible positioning of therapeutics targeting IL-33 or its receptor in the expanding landscape of novel biologicals applied in asthma management.
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人脐带间充质干细胞的外泌体通过重塑巨噬细胞极化来减轻重度激素抵抗性哮喘的炎症
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TRPA1抑制剂通过抑制哮喘治疗中的神经源性炎症和气道收缩治疗哮喘
