LTβR信号直接控制气道平滑肌失调和哮喘肺功能障碍
2022/12/21
摘要
背景：气道平滑肌细胞（ASM）失调是哮喘严重程度的关键。哪些分子主要控制哮喘患者的ASM尚不清楚。高水平的细胞因子LIGHT（TNFSF14）与哮喘严重程度和较低的基线FEV1%预测相关，这意味着通过其受体的信号可能直接控制ASM功能障碍。
目的：确定来自LIGHT的LTβR或HVEM信号是否主要驱动过敏原诱导的ASM高反应性。
方法：使用平滑肌细胞中缺乏LTβR或HVEM的条件性敲除小鼠来确定它们在体内ASM失调和气道高反应性（AHR）中的作用。人ASM用于研究LTβR诱导的信号。
结果：与其他几种与平滑肌失调有关的受体相比，LTβR在正常和哮喘患者的ASM中强烈表达。相应地，仅在smMHCCreLTβRfl/fl小鼠的平滑肌细胞中有条件地缺失LTβR使得其数量和质量的变化最小化，并且在严重哮喘模型中由屋尘螨过敏原诱导的AHR最小化。气管内LIGHT给药独立地诱导体内ASM肥大和AHR，这取决于对ASM的直接LTβR信号。LIGHT在体外促进人ASM的收缩性，肥大和增生。区分LTβR与也与平滑肌失调有关的IL-13，TNF和IL-17受体，LIGHT在体外促进ASM中NIK依赖性非经典NF-κB，导致F-肌动蛋白的持续积累。，肌球蛋白轻链激酶的磷酸化和收缩活性。
结论：LTβR信号直接和主导地驱动气道平滑肌高反应性，与重症哮喘气道重塑的发病机制相关。
LTβR Signaling Directly Controls Airway Smooth Muscle Deregulation and Asthmatic Lung Dysfunction
Haruka Miki, William B Kiosses, Mario C Manresa, Rinkesh K Gupta, Gurupreet S Sethi, Rana Herro, Ricardo Da Silva Antunes, Paramita Dutta, Marina Miller, Kai Fung, Ashu Chawla, Katarzyna Dobaczewska, Ferhat Ay, David H Broide, Alexei V Tumanov, Michael Croft
Abstract
Background: Dysregulation of airway smooth muscle cells (ASM) is central to the severity of asthma. Which molecules dominantly control ASM in asthmatics is unclear. High levels of the cytokine LIGHT (TNFSF14) have been linked to asthma severity and lower baseline FEV1% predicted, implying signals through its receptors might directly control ASM dysfunction.
Objective: To determine whether signaling via LTβR or HVEM from LIGHT dominantly drives ASM hyperreactivity induced by allergen.
Methods: Conditional knockout mice deficient for LTβR or HVEM in smooth muscle cells were used to determine their role in ASM deregulation and airway hyperresponsiveness (AHR) in vivo. Human ASM were used to study signals induced by LTβR.
Results: LTβR was strongly expressed in ASM from normal and asthmatic subjects compared to several other receptors implicated in smooth muscle deregulation. Correspondingly, conditional deletion of LTβR only in smooth muscle cells in smMHCCreLTβRfl/fl mice minimized changes in their numbers and mass, and AHR, induced by house dust mite allergen in a model of severe asthma. Intratracheal LIGHT administration independently induced ASM hypertrophy and AHR in vivo dependent on direct LTβR signals to ASM. LIGHT promoted contractility, hypertrophy, and hyperplasia of human ASM in vitro. Distinguishing LTβR from the receptors for IL-13, TNF, and IL-17 that have also been implicated in smooth muscle dysregulation, LIGHT promoted NIK-dependent non-canonical NF-κB in ASM in vitro, leading to sustained accumulation of F-actin, phosphorylation of myosin light chain kinase, and contractile activity.
Conclusion: LTβR signals directly and dominantly drive airway smooth muscle hyperresponsiveness relevant for pathogenesis of airway remodeling in severe asthma.
背景：气道平滑肌细胞（ASM）失调是哮喘严重程度的关键。哪些分子主要控制哮喘患者的ASM尚不清楚。高水平的细胞因子LIGHT（TNFSF14）与哮喘严重程度和较低的基线FEV1%预测相关，这意味着通过其受体的信号可能直接控制ASM功能障碍。
目的：确定来自LIGHT的LTβR或HVEM信号是否主要驱动过敏原诱导的ASM高反应性。
方法：使用平滑肌细胞中缺乏LTβR或HVEM的条件性敲除小鼠来确定它们在体内ASM失调和气道高反应性（AHR）中的作用。人ASM用于研究LTβR诱导的信号。
结果：与其他几种与平滑肌失调有关的受体相比，LTβR在正常和哮喘患者的ASM中强烈表达。相应地，仅在smMHCCreLTβRfl/fl小鼠的平滑肌细胞中有条件地缺失LTβR使得其数量和质量的变化最小化，并且在严重哮喘模型中由屋尘螨过敏原诱导的AHR最小化。气管内LIGHT给药独立地诱导体内ASM肥大和AHR，这取决于对ASM的直接LTβR信号。LIGHT在体外促进人ASM的收缩性，肥大和增生。区分LTβR与也与平滑肌失调有关的IL-13，TNF和IL-17受体，LIGHT在体外促进ASM中NIK依赖性非经典NF-κB，导致F-肌动蛋白的持续积累。，肌球蛋白轻链激酶的磷酸化和收缩活性。
结论：LTβR信号直接和主导地驱动气道平滑肌高反应性，与重症哮喘气道重塑的发病机制相关。
(中日友好医院呼吸与危重症医学科 李红雯 摘译 林江涛 审校)
(J Allergy Clin Immunol. 2022 Dec 3;S0091-6749(22)01622-0. doi: 10.1016/j.jaci.2022.11.016.)
(J Allergy Clin Immunol. 2022 Dec 3;S0091-6749(22)01622-0. doi: 10.1016/j.jaci.2022.11.016.)
LTβR Signaling Directly Controls Airway Smooth Muscle Deregulation and Asthmatic Lung Dysfunction
Haruka Miki, William B Kiosses, Mario C Manresa, Rinkesh K Gupta, Gurupreet S Sethi, Rana Herro, Ricardo Da Silva Antunes, Paramita Dutta, Marina Miller, Kai Fung, Ashu Chawla, Katarzyna Dobaczewska, Ferhat Ay, David H Broide, Alexei V Tumanov, Michael Croft
Abstract
Background: Dysregulation of airway smooth muscle cells (ASM) is central to the severity of asthma. Which molecules dominantly control ASM in asthmatics is unclear. High levels of the cytokine LIGHT (TNFSF14) have been linked to asthma severity and lower baseline FEV1% predicted, implying signals through its receptors might directly control ASM dysfunction.
Objective: To determine whether signaling via LTβR or HVEM from LIGHT dominantly drives ASM hyperreactivity induced by allergen.
Methods: Conditional knockout mice deficient for LTβR or HVEM in smooth muscle cells were used to determine their role in ASM deregulation and airway hyperresponsiveness (AHR) in vivo. Human ASM were used to study signals induced by LTβR.
Results: LTβR was strongly expressed in ASM from normal and asthmatic subjects compared to several other receptors implicated in smooth muscle deregulation. Correspondingly, conditional deletion of LTβR only in smooth muscle cells in smMHCCreLTβRfl/fl mice minimized changes in their numbers and mass, and AHR, induced by house dust mite allergen in a model of severe asthma. Intratracheal LIGHT administration independently induced ASM hypertrophy and AHR in vivo dependent on direct LTβR signals to ASM. LIGHT promoted contractility, hypertrophy, and hyperplasia of human ASM in vitro. Distinguishing LTβR from the receptors for IL-13, TNF, and IL-17 that have also been implicated in smooth muscle dysregulation, LIGHT promoted NIK-dependent non-canonical NF-κB in ASM in vitro, leading to sustained accumulation of F-actin, phosphorylation of myosin light chain kinase, and contractile activity.
Conclusion: LTβR signals directly and dominantly drive airway smooth muscle hyperresponsiveness relevant for pathogenesis of airway remodeling in severe asthma.
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非严重哮喘成人血浆胸腺基质淋巴细胞生成素（TSLP）：EGEA研究
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