CCL5是哮喘中1型和2型炎症之间的潜在桥梁
2023/03/21
摘要
背景：T1炎症（以IFN-γ表达为标志）目前在哮喘队列的亚群中得到一致鉴定，但其如何导致疾病仍不清楚。
目的：我们试图了解CCL5在哮喘T1炎症中的作用，以及它如何与T1和T2炎症相互作用。
方法：痰液大量RNAseq中CCL5、CXCL9和CXCL10 mRNA的表达以及临床/炎症数据来自重症哮喘研究计划（SARPIII）。支气管肺泡灌洗液（BAL）细胞体RNAseq的CCL5和IFNG表达数据来自重症哮喘免疫机制（IMSA）队列，该表达数据与先前确定的免疫细胞谱相关。在小鼠高T1重症哮喘模型中评估CCL5在组织驻留记忆T细胞（TRMs）再激活中的作用。
结果：痰液CCL5表达与T1趋化因子密切相关（CXCL9和CXCL10的p<0.001），这与T1炎症中的作用一致。除了痰嗜中性粒细胞（p=0.001）外，CCL5高参与者的FeNO（p=0.009）、血嗜酸性粒细胞（p<0.001）和痰嗜酸性粒粒细胞（p=0.001）更高。CCL5 BAL表达增加是IMSA队列中先前描述的T1High/T2变量/淋巴细胞患者组独有的，IFNG仅在这一组出现肺阻塞恶化的趋势（p=0.083）。在小鼠模型中，在TRM中观察到CCL5受体CCR5的高表达，并且与T1特征一致。CCR5抑制剂maraviroc阻断再激活的能力支持CCL5在TRM激活中的作用。
结论：CCL5似乎与哮喘TRM相关的T1中性粒细胞炎症有关，但矛盾的是，CCL5也与T2炎症和痰液嗜酸性粒细胞增多有关。
CCL5 is a Potential Bridge Between Type-1 and Type-2 Inflammation in Asthma
Marc Gauthier, Sagar Laxman Kale, Timothy B Oriss, Michael Gorry, Richard P Ramonell, Kathryn Dalton, Prabir Ray, John V Fahy, Max A Seibold, Mario Castro, Nizar Jarjour, Benjamin Gaston, Eugene R Bleecker, Deborah A Meyers, Wendy Moore, Annette T Hastie, Elliot Israel, Bruce D Levy, David Mauger, Serpil Erzurum, Suzy A Comhair, Sally E Wenzel, Anuradha Ray
Abstract
Background: T1 inflammation (marked by IFN-γ expression) is now consistently identified in subsets of asthma cohorts, but how it contributes to disease remains unclear.
Objective: We sought to understand the role of CCL5 in asthmatic T1 inflammation, and how it interacts with both T1 and T2 inflammation.
Methods: CCL5, CXCL9 and CXCL10 mRNA expression from sputum bulk RNAseq, as well as clinical/inflammatory data were obtained from the Severe Asthma Research Program (SARPIII). CCL5 and IFNG expression from Bronchoalveolar lavage (BAL) cell bulk RNAseq were 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-cells (TRMs) reactivation was evaluated in a T1 high murine severe asthma model.
Results: Sputum CCL5 expression strongly correlated with T1 chemokines (p<0.001 for CXCL9 and CXCL10), consistent with a role in T1 inflammation. CCL5High participants had greater FeNO (p=0.009), blood eosinophils (p<0.001), and sputum eosinophils (p=0.001) in addition to sputum neutrophils (p=0.001). Increased CCL5 BAL 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=0.083). In a murine model, high expression of the CCL5 receptor CCR5 was observed in TRMs and 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.
Conclusion: 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：T1炎症（以IFN-γ表达为标志）目前在哮喘队列的亚群中得到一致鉴定，但其如何导致疾病仍不清楚。
目的：我们试图了解CCL5在哮喘T1炎症中的作用，以及它如何与T1和T2炎症相互作用。
方法：痰液大量RNAseq中CCL5、CXCL9和CXCL10 mRNA的表达以及临床/炎症数据来自重症哮喘研究计划（SARPIII）。支气管肺泡灌洗液（BAL）细胞体RNAseq的CCL5和IFNG表达数据来自重症哮喘免疫机制（IMSA）队列，该表达数据与先前确定的免疫细胞谱相关。在小鼠高T1重症哮喘模型中评估CCL5在组织驻留记忆T细胞（TRMs）再激活中的作用。
结果：痰液CCL5表达与T1趋化因子密切相关（CXCL9和CXCL10的p<0.001），这与T1炎症中的作用一致。除了痰嗜中性粒细胞（p=0.001）外，CCL5高参与者的FeNO（p=0.009）、血嗜酸性粒细胞（p<0.001）和痰嗜酸性粒粒细胞（p=0.001）更高。CCL5 BAL表达增加是IMSA队列中先前描述的T1High/T2变量/淋巴细胞患者组独有的，IFNG仅在这一组出现肺阻塞恶化的趋势（p=0.083）。在小鼠模型中，在TRM中观察到CCL5受体CCR5的高表达，并且与T1特征一致。CCR5抑制剂maraviroc阻断再激活的能力支持CCL5在TRM激活中的作用。
结论：CCL5似乎与哮喘TRM相关的T1中性粒细胞炎症有关，但矛盾的是，CCL5也与T2炎症和痰液嗜酸性粒细胞增多有关。
(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)
(J Allergy Clin Immunol. 2023 Mar 7;S0091-6749(23)00289-0. doi: 10.1016/j.jaci.2023.02.028.)
(J Allergy Clin Immunol. 2023 Mar 7;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
Marc Gauthier, Sagar Laxman Kale, Timothy B Oriss, Michael Gorry, Richard P Ramonell, Kathryn Dalton, Prabir Ray, John V Fahy, Max A Seibold, Mario Castro, Nizar Jarjour, Benjamin Gaston, Eugene R Bleecker, Deborah A Meyers, Wendy Moore, Annette T Hastie, Elliot Israel, Bruce D Levy, David Mauger, Serpil Erzurum, Suzy A Comhair, Sally E Wenzel, Anuradha Ray
Abstract
Background: T1 inflammation (marked by IFN-γ expression) is now consistently identified in subsets of asthma cohorts, but how it contributes to disease remains unclear.
Objective: We sought to understand the role of CCL5 in asthmatic T1 inflammation, and how it interacts with both T1 and T2 inflammation.
Methods: CCL5, CXCL9 and CXCL10 mRNA expression from sputum bulk RNAseq, as well as clinical/inflammatory data were obtained from the Severe Asthma Research Program (SARPIII). CCL5 and IFNG expression from Bronchoalveolar lavage (BAL) cell bulk RNAseq were 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-cells (TRMs) reactivation was evaluated in a T1 high murine severe asthma model.
Results: Sputum CCL5 expression strongly correlated with T1 chemokines (p<0.001 for CXCL9 and CXCL10), consistent with a role in T1 inflammation. CCL5High participants had greater FeNO (p=0.009), blood eosinophils (p<0.001), and sputum eosinophils (p=0.001) in addition to sputum neutrophils (p=0.001). Increased CCL5 BAL 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=0.083). In a murine model, high expression of the CCL5 receptor CCR5 was observed in TRMs and 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.
Conclusion: CCL5 appears to contribute to TRM-related T1 neutrophilic inflammation in asthma, while paradoxically also correlating with T2 inflammation and with sputum eosinophilia.
上一篇：
伴有症状性嗜酸性粒细胞炎症的成人哮喘肠道微生物组的改变
下一篇：
心肌素调节气道平滑肌细胞重塑以应对慢性哮喘损伤
