Chu Derek K, Al-Garawi Amal, Llop-Guevara Alba, Pillai Regina A, Radford Katherine, Shen Pamela, Walker Tina D, Goncharova Susanna, Calhoun William J, Nair Parameswaran, Jordana Manel
Department of Pathology & Molecular Medicine, McMaster Immunology Research Centre, Hamilton, ON Canada.
Division of Pulmonary and Critical Care Medicine, and Institute for Translational Sciences, University of Texas Medical Branch, Galveston, Texas USA.
Allergy Asthma Clin Immunol. 2015 Apr 12;11(1):14. doi: 10.1186/s13223-015-0081-1. eCollection 2015.
Determining the cellular and molecular phenotypes of inflammation in asthma can identify patient populations that may best benefit from targeted therapies. Although elevated IL-6 and polymorphisms in IL-6 signalling are associated with lung dysfunction in asthma, it remains unknown if elevated IL-6 levels are associated with a specific cellular inflammatory phenotype, and how IL-6 blockade might impact such inflammatory responses.
Patients undergoing exacerbations of asthma were phenotyped according to their airway inflammatory characteristics (normal cell count, eosinophilic, neutrophilic, mixed granulocytic), sputum cytokine profiles, and lung function. Mice were exposed to the common allergen, house dust-mite (HDM), in the presence or absence of endogenous IL-6. The intensity and nature of lung inflammation, and levels of pro-granulocytic cytokines and chemokines under these conditions were analyzed.
Elevated IL-6 was associated with a lower FEV1 in patients with mixed eosinophilic-neutrophilic bronchitis. In mice, allergen exposure increased lung IL-6 and IL-6 was produced by dendritic cells and alveolar macrophages. Loss-of-function of IL-6 signalling (knockout or antibody-mediated neutralization) abrogated elevations of eosinophil and neutrophil recruiting cytokines/chemokines and allergen-induced airway inflammation in mice.
We demonstrate the association of pleiotropic cellular airway inflammation with IL-6 using human and animal data. These data suggest that exacerbations of asthma, particularly those with a combined eosinophilic and neutrophilic bronchitis, may respond to therapies targeting the IL-6 pathway and therefore, provide a rational basis for initiation of clinical trials to evaluate this.
确定哮喘炎症的细胞和分子表型可识别可能从靶向治疗中获益最大的患者群体。尽管白细胞介素-6（IL-6）升高以及IL-6信号通路中的多态性与哮喘肺功能障碍相关，但IL-6水平升高是否与特定的细胞炎症表型相关，以及IL-6阻断如何影响此类炎症反应仍不清楚。
根据哮喘加重期患者的气道炎症特征（正常细胞计数、嗜酸性粒细胞性、中性粒细胞性、混合粒细胞性）、痰液细胞因子谱和肺功能进行表型分析。在有或无内源性IL-6的情况下，将小鼠暴露于常见变应原屋尘螨（HDM）。分析这些条件下肺炎症的强度和性质以及促粒细胞细胞因子和趋化因子的水平。
在嗜酸性粒细胞-中性粒细胞混合性支气管炎患者中，IL-6升高与第一秒用力呼气容积（FEV1）降低相关。在小鼠中，变应原暴露增加肺IL-6，且IL-6由树突状细胞和肺泡巨噬细胞产生。IL-6信号通路功能丧失（基因敲除或抗体介导的中和）消除了嗜酸性粒细胞和中性粒细胞募集细胞因子/趋化因子的升高以及变应原诱导的小鼠气道炎症。
我们利用人和动物数据证明了多效性细胞气道炎症与IL-6之间的关联。这些数据表明，哮喘加重期，尤其是那些合并嗜酸性粒细胞性和中性粒细胞性支气管炎的患者，可能对靶向IL-6途径的治疗有反应，因此，为启动评估此治疗方法的临床试验提供了合理依据。
