CCL5可作为支气管哮喘1型炎症和2型炎症之间的潜在桥梁
2023/05/25
摘要
背景：目前，支气管哮喘（哮喘）队列的亚群均发现以IFN-γ表达为标志的1型（T1）炎症，但其致病机制尚不清楚。本研究旨在探索CCL5在哮喘T1炎症中的作用，及其与T1、2型（T2）炎症的相互作用。
方法：本研究所用痰液批量RNA测序中CCL5、CXCL9和CXCL10信使RNA的表达情况，及临床、炎症数据来自重症哮喘研究计划III（SARP III）。支气管肺泡灌洗液细胞批量RNA测序中CCL5和IFNG的表达情况来自重症哮喘的免疫机制（IMSA）队列以及既往已鉴定免疫细胞谱相关表达。通过高T1小鼠重症哮喘模型评估CCL5在组织驻留记忆T细胞（TRM）再激活中的作用。
结果：痰CCL5的表达与T1趋化因子密切相关（CXCL9和CXCL10 P<.001），这与其在T1炎症中的作用一致。高CCL5受试者呼出气一氧化氮水平（P=0.009）、外周血嗜酸性粒细胞（P<.001）、痰嗜酸性粒粒细胞（P=.001）及痰中性粒细胞（P=0.001）更高。支气管肺泡灌洗液中CCL5 表达增加，仅见于IMSA队列中预先定义的高T1/可变T2/淋巴细胞患者组。在小鼠模型中观察到CCL5受体CCR5在TRM中高表达，且与T1炎症特征一致。CCR5抑制剂马拉韦罗抑制可抑制TRM再激活，支持CCL5在TRM激活中的作用。
结论：本研究显示，CCL5有助于哮喘中TRM相关T1中性粒细胞炎症，同时也与T2炎症和痰嗜酸性粒细胞增多症相关。
CCL5 is a potential bridge between type 1 and type 2 inflammation in asthma.
Gauthier M, Kale SL, Oriss TB, Gorry M, Ramonell RP, Dalton K, Ray P, Fahy JV, Seibold MA, Castro M, Jarjour N, Gaston B, Bleecker ER, Meyers DA, Moore W, Hastie AT, Israel E, Levy BD, Mauger D, Erzurum S, Comhair SA, Wenzel SE, Ray A.
Abstract
BACKGROUND:Type 1 (T1) inflammation (marked by IFN-γ expression) is now consistently identified in subsets of asthma cohorts, but how it contributes to disease remains unclear. We sought to understand the role of CCL5 in asthmatic T1 inflammation and how it interacts with both T1 and type 2 (T2) inflammation.
METHODS:CCL5, CXCL9, and CXCL10 messenger RNA expression from sputum bulk RNA sequencing, as well as clinical and inflammatory data were obtained from the Severe Asthma Research Program III (SARP III). CCL5 and IFNG expression from bronchoalveolar lavage cell bulk RNA sequencing was obtained from the Immune Mechanisms in Severe Asthma (IMSA) cohort and expression related to previously identified immune cell profiles. The role of CCL5 in tissue-resident memory T-cell (TRM) reactivation was evaluated in a T1high murine severe asthma model.
RESULTS:Sputum CCL5 expression strongly correlated with T1 chemokines (P < .001 for CXCL9 and CXCL10), consistent with a role in T1 inflammation. CCL5high participants had greater fractional exhaled nitric oxide (P = .009), blood eosinophils (P < .001), and sputum eosinophils (P = .001) in addition to sputum neutrophils (P = .001). Increased CCL5 bronchoalveolar lavage expression was unique to a previously described T1high/T2variable/lymphocytic patient group in the IMSA cohort, with IFNG trending with worsening lung obstruction only in this group (P = .083). In a murine model, high expression of the CCL5 receptor CCR5 was observed in TRMs and was consistent with a T1 signature. A role for CCL5 in TRM activation was supported by the ability of the CCR5 inhibitor maraviroc to blunt reactivation.
CONCLUSIONS:CCL5 appears to contribute to TRM-related T1 neutrophilic inflammation in asthma while paradoxically also correlating with T2 inflammation and with sputum eosinophilia.
背景：目前，支气管哮喘（哮喘）队列的亚群均发现以IFN-γ表达为标志的1型（T1）炎症，但其致病机制尚不清楚。本研究旨在探索CCL5在哮喘T1炎症中的作用，及其与T1、2型（T2）炎症的相互作用。
方法：本研究所用痰液批量RNA测序中CCL5、CXCL9和CXCL10信使RNA的表达情况，及临床、炎症数据来自重症哮喘研究计划III（SARP III）。支气管肺泡灌洗液细胞批量RNA测序中CCL5和IFNG的表达情况来自重症哮喘的免疫机制（IMSA）队列以及既往已鉴定免疫细胞谱相关表达。通过高T1小鼠重症哮喘模型评估CCL5在组织驻留记忆T细胞（TRM）再激活中的作用。
结果：痰CCL5的表达与T1趋化因子密切相关（CXCL9和CXCL10 P<.001），这与其在T1炎症中的作用一致。高CCL5受试者呼出气一氧化氮水平（P=0.009）、外周血嗜酸性粒细胞（P<.001）、痰嗜酸性粒粒细胞（P=.001）及痰中性粒细胞（P=0.001）更高。支气管肺泡灌洗液中CCL5 表达增加，仅见于IMSA队列中预先定义的高T1/可变T2/淋巴细胞患者组。在小鼠模型中观察到CCL5受体CCR5在TRM中高表达，且与T1炎症特征一致。CCR5抑制剂马拉韦罗抑制可抑制TRM再激活，支持CCL5在TRM激活中的作用。
结论：本研究显示，CCL5有助于哮喘中TRM相关T1中性粒细胞炎症，同时也与T2炎症和痰嗜酸性粒细胞增多症相关。
(中日友好医院呼吸与危重症医学科 张婧媛 摘译 林江涛 审校)
(J Allergy Clin Immunol. 2023 Mar 8:S0091-6749(23)00289-0. doi: 10.1016/j.jaci.2023.02.028.)
(J Allergy Clin Immunol. 2023 Mar 8:S0091-6749(23)00289-0. doi: 10.1016/j.jaci.2023.02.028.)
CCL5 is a potential bridge between type 1 and type 2 inflammation in asthma.
Gauthier M, Kale SL, Oriss TB, Gorry M, Ramonell RP, Dalton K, Ray P, Fahy JV, Seibold MA, Castro M, Jarjour N, Gaston B, Bleecker ER, Meyers DA, Moore W, Hastie AT, Israel E, Levy BD, Mauger D, Erzurum S, Comhair SA, Wenzel SE, Ray A.
Abstract
BACKGROUND:Type 1 (T1) inflammation (marked by IFN-γ expression) is now consistently identified in subsets of asthma cohorts, but how it contributes to disease remains unclear. We sought to understand the role of CCL5 in asthmatic T1 inflammation and how it interacts with both T1 and type 2 (T2) inflammation.
METHODS:CCL5, CXCL9, and CXCL10 messenger RNA expression from sputum bulk RNA sequencing, as well as clinical and inflammatory data were obtained from the Severe Asthma Research Program III (SARP III). CCL5 and IFNG expression from bronchoalveolar lavage cell bulk RNA sequencing was obtained from the Immune Mechanisms in Severe Asthma (IMSA) cohort and expression related to previously identified immune cell profiles. The role of CCL5 in tissue-resident memory T-cell (TRM) reactivation was evaluated in a T1high murine severe asthma model.
RESULTS:Sputum CCL5 expression strongly correlated with T1 chemokines (P < .001 for CXCL9 and CXCL10), consistent with a role in T1 inflammation. CCL5high participants had greater fractional exhaled nitric oxide (P = .009), blood eosinophils (P < .001), and sputum eosinophils (P = .001) in addition to sputum neutrophils (P = .001). Increased CCL5 bronchoalveolar lavage expression was unique to a previously described T1high/T2variable/lymphocytic patient group in the IMSA cohort, with IFNG trending with worsening lung obstruction only in this group (P = .083). In a murine model, high expression of the CCL5 receptor CCR5 was observed in TRMs and was consistent with a T1 signature. A role for CCL5 in TRM activation was supported by the ability of the CCR5 inhibitor maraviroc to blunt reactivation.
CONCLUSIONS:CCL5 appears to contribute to TRM-related T1 neutrophilic inflammation in asthma while paradoxically also correlating with T2 inflammation and with sputum eosinophilia.
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传统农场环境灰尘中的哮喘保护剂
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Th2型炎症通过纤毛上皮细胞的功能的改变减少过敏性哮喘气道上皮中SARS-CoV-2的复制
