不同的上皮先天免疫细胞转录回路是哮喘气道高反应性的基础
2023/06/25
摘要
理由：间接气道高反应性（AHR）是哮喘的一个高度特异性特征，但导致间接AHR的潜在机制尚不完全清楚。
目的：确定从哮喘患者获得的上皮细胞中基因表达的差异，这些患者以运动诱导的支气管收缩（EIB）的形式表现为间接AHR。
方法：对哮喘患者（n=11）和无EIB（n=9）获得的上皮刷检进行RNA测序（RNA-seq）分析。差异表达基因（DEGs）与气道生理学，痰液炎症标志物和气道壁免疫病理学的测量相关。基于这些关系，我们检查了原代气道上皮细胞（AECs）和特定上皮衍生细胞因子对肥大细胞（MCs）和嗜酸性粒细胞（EOS）的影响。
结果：我们在有和没有EIB的个体之间确定了120个DEG。网络分析表明IL-33、IL-18和IFN与这些DEG之间的相关信号显著相关。IL1RL1表达与上皮区室中MC的密度呈正相关，IL1RL1，IL18R1和IFNG与上皮内EO的密度呈正相关。随后的离体建模表明，AEC促进MC中持续的T2炎症并增强IL-33诱导的T2基因表达。此外，EOS响应于IL-18和IL-33以及暴露于AEC而增加IFNG和IL13的表达。
结论：涉及上皮与MCs和EOS相互作用的回路与间接AHR密切相关。离体建模表明，这些先天细胞的上皮依赖性调节可能在间接AHR和调节哮喘中的T2和非T2炎症中至关重要。
Distinct Epithelial-Innate Immune Cell Transcriptional Circuits Underlie Airway Hyperresponsiveness in Asthma
Ryan C Murphy, Ying Lai, Matthew Liu, Taha Al-Shaikhly, Matthew C Altman, William A Altemeier, Charles W Frevert, Jason S Debley, Adrian M Piliponsky, Steven F Ziegler, Sina A Gharib, Teal S Hallstrand
Abstract
Rationale: Indirect airway hyperresponsiveness (AHR) is a highly specific feature of asthma but the underlying mechanisms responsible for driving indirect AHR remain incompletely understood.
Objectives: Identify differences in gene expression in epithelial brushings obtained from individuals with asthma who were characterized for indirect AHR in the form of exercise-induced bronchoconstriction (EIB).
Methods: RNA-sequencing (RNA-seq) analysis was performed on epithelial brushings obtained from asthmatic individuals with (n=11) and without EIB (n = 9). Differentially expressed genes (DEGs) were correlated with measures of airway physiology, sputum inflammatory markers, and airway wall immunopathology. Based on these relationships, we examined the effects of primary airway epithelial cells (AECs) and specific epithelial-derived cytokines on both mast cells (MCs) and eosinophils (EOS).
Results: We identified 120 DEGs between individuals with and without EIB. Network analyses suggested critical roles for IL-33-, IL-18-, and IFN--related signaling amongst these DEGs. IL1RL1 expression was positively correlated with the density of MCs in the epithelial compartment and IL1RL1, IL18R1, and IFNG were positively correlated with the density of intraepithelial EOS. Subsequent ex vivo modeling demonstrated that AECs promote sustained T2 inflammation in MCs and enhance IL-33-induced T2 gene expression. Further, EOS increase expression of IFNG and IL13 in response to both IL-18 and IL-33 as well as exposure to AECs.
Conclusions: Circuits involving epithelial interactions with MCs and EOS are closely associated with indirect AHR. Ex vivo modeling indicates that epithelial-dependent regulation of these innate cells may be critical in indirect AHR and modulating T2 and non-T2 inflammation in asthma.
理由：间接气道高反应性（AHR）是哮喘的一个高度特异性特征，但导致间接AHR的潜在机制尚不完全清楚。
目的：确定从哮喘患者获得的上皮细胞中基因表达的差异，这些患者以运动诱导的支气管收缩（EIB）的形式表现为间接AHR。
方法：对哮喘患者（n=11）和无EIB（n=9）获得的上皮刷检进行RNA测序（RNA-seq）分析。差异表达基因（DEGs）与气道生理学，痰液炎症标志物和气道壁免疫病理学的测量相关。基于这些关系，我们检查了原代气道上皮细胞（AECs）和特定上皮衍生细胞因子对肥大细胞（MCs）和嗜酸性粒细胞（EOS）的影响。
结果：我们在有和没有EIB的个体之间确定了120个DEG。网络分析表明IL-33、IL-18和IFN与这些DEG之间的相关信号显著相关。IL1RL1表达与上皮区室中MC的密度呈正相关，IL1RL1，IL18R1和IFNG与上皮内EO的密度呈正相关。随后的离体建模表明，AEC促进MC中持续的T2炎症并增强IL-33诱导的T2基因表达。此外，EOS响应于IL-18和IL-33以及暴露于AEC而增加IFNG和IL13的表达。
结论：涉及上皮与MCs和EOS相互作用的回路与间接AHR密切相关。离体建模表明，这些先天细胞的上皮依赖性调节可能在间接AHR和调节哮喘中的T2和非T2炎症中至关重要。
(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)
(Am J Respir Crit Care Med. 2023 May 22. doi: 10.1164/rccm.202209-1707OC.)
(Am J Respir Crit Care Med. 2023 May 22. doi: 10.1164/rccm.202209-1707OC.)
Distinct Epithelial-Innate Immune Cell Transcriptional Circuits Underlie Airway Hyperresponsiveness in Asthma
Ryan C Murphy, Ying Lai, Matthew Liu, Taha Al-Shaikhly, Matthew C Altman, William A Altemeier, Charles W Frevert, Jason S Debley, Adrian M Piliponsky, Steven F Ziegler, Sina A Gharib, Teal S Hallstrand
Abstract
Rationale: Indirect airway hyperresponsiveness (AHR) is a highly specific feature of asthma but the underlying mechanisms responsible for driving indirect AHR remain incompletely understood.
Objectives: Identify differences in gene expression in epithelial brushings obtained from individuals with asthma who were characterized for indirect AHR in the form of exercise-induced bronchoconstriction (EIB).
Methods: RNA-sequencing (RNA-seq) analysis was performed on epithelial brushings obtained from asthmatic individuals with (n=11) and without EIB (n = 9). Differentially expressed genes (DEGs) were correlated with measures of airway physiology, sputum inflammatory markers, and airway wall immunopathology. Based on these relationships, we examined the effects of primary airway epithelial cells (AECs) and specific epithelial-derived cytokines on both mast cells (MCs) and eosinophils (EOS).
Results: We identified 120 DEGs between individuals with and without EIB. Network analyses suggested critical roles for IL-33-, IL-18-, and IFN--related signaling amongst these DEGs. IL1RL1 expression was positively correlated with the density of MCs in the epithelial compartment and IL1RL1, IL18R1, and IFNG were positively correlated with the density of intraepithelial EOS. Subsequent ex vivo modeling demonstrated that AECs promote sustained T2 inflammation in MCs and enhance IL-33-induced T2 gene expression. Further, EOS increase expression of IFNG and IL13 in response to both IL-18 and IL-33 as well as exposure to AECs.
Conclusions: Circuits involving epithelial interactions with MCs and EOS are closely associated with indirect AHR. Ex vivo modeling indicates that epithelial-dependent regulation of these innate cells may be critical in indirect AHR and modulating T2 and non-T2 inflammation in asthma.
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中性粒细胞外陷阱的产生和CCL4L2的表达对哮喘皮质类固醇反应的影响
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