RANKL通过激活肺泡巨噬细胞促进慢阻肺气道炎症
2026/07/31
摘要
背景：慢性气道炎症是慢性阻塞性肺疾病（COPD）发病及进展的关键驱动因素。肺泡巨噬细胞（AMs）的活化状态以及炎性细胞因子释放是该过程中的关键表型特征。尽管RANKL已被证实参与免疫调控及细胞因子分泌，但其在AMs促炎性激活中的具体作用，以及与COPD气道炎症的关联，尚不明确。本研究旨在探讨COPD中的RANKL通路，并阐明其在激活AM和气道炎症中的作用。
方法：首先，作者在肺组织中定量并定位RANKL及其受体RANK，同时评估COPD患者、吸烟者及非吸烟者的支气管肺泡灌洗液中CD86相关的促炎性巨噬细胞激活水平。随后，将野生型小鼠暴露于空气或香烟烟雾（CS）24周。在暴露于CS小鼠中，腹腔注射抗小鼠RANKL单克隆抗体或大鼠IgG2a kappa同型对照抗体，进一步评估巨噬细胞激活情况及气道炎症水平。最后，在体外实验中探讨RANKL在CS诱导的促炎性巨噬细胞激活及气道炎症中的生物学功能。
结果：研究发现，在COPD患者肺组织中，RANKL及RANK表达水平升高，同时CD86相关的促炎性巨噬细胞激活增强。RANKL及RANK主要定位于AMs。CS暴露显著增强小鼠的促炎性巨噬细胞激活及气道炎症，而使用抗RANKL单克隆抗体可减轻这些影响。在体外实验中，香烟烟雾提取物（CSE）上调AMs中RANKL及RANK的表达。AMs在RANKL或CSE刺激下呈促炎性活化状态，且细胞因子表达增加。此外，中和抗RANKL单克隆抗体可部分抑制CSE诱导的促炎性巨噬细胞激活及细胞因子表达。
结论：RANKL通过促炎性肺泡巨噬细胞激活参与COPD气道炎症。本研究加深了对RANKL通路在气道炎症中作用的认识，并提示RANKL可能成为COPD的潜在治疗靶点。
关键词：气道炎症；肺泡巨噬细胞；COPD；促炎性巨噬细胞激活；RANKL
Background: Chronic airway inflammation is a key mechanism involved in the pathogenesis and progression of chronic obstructive pulmonary disease (COPD). Altered activation states of alveolar macrophages (AMs) and the release of inflammatory cytokines represent critical phenotypes in this inflammatory process. Although RANKL is known to participate in immune regulation and cytokine secretion, its potential involvement in pro-inflammatory activation of AMs and the associated contribution to airway inflammation in COPD remains incompletely understood. The purpose of this study is to investigate the RANKL pathway in COPD and to elucidate its role in AM activation and airway inflammation.
Methods: First, we quantified and localized RANKL and its receptor RANK in lung tissues and assessed CD86-associated pro-inflammatory macrophage activation in bronchoalveolar lavage fluid from COPD patients, smokers, and non-smokers. Next, wild-type mice were exposed to either air or cigarette smoke (CS) for 24 weeks. CS-exposed mice received intraperitoneal injections of either an anti-mouse RANKL monoclonal antibody or a rat IgG2a kappa isotype control antibody; macrophage activation status and airway inflammation were subsequently evaluated. Finally, we investigated the in vitro biological function of RANKL in CS-induced pro-inflammatory macrophage activation and airway inflammation.
Results: We found that the expression of both RANKL and RANK, along with enhanced CD86-associated pro-inflammatory macrophage activation, was increased in the lung tissues of COPD patients. In these tissues, RANKL and RANK were localized to AMs. In CS-exposed mice, pro-inflammatory macrophage activation and airway inflammation were significantly increased; however, these effects were ameliorated in CS-exposed mice treated with the anti-RANKL monoclonal antibody. In vitro, cigarette smoke extract (CSE) up-regulated the expression of RANKL and RANK in AMs. AMs responded to CSE and RANKL stimulation by exhibiting pro-inflammatory activation and enhanced cytokine expression. Furthermore, CSE-induced pro-inflammatory macrophage activation and cytokine expression were partially inhibited by the addition of a neutralizing anti-RANKL monoclonal antibody.
Conclusion: RANKL contributes to airway inflammation through pro-inflammatory alveolar macrophage activation in COPD. These findings extend current understanding of the role of the RANKL pathway in airway inflammation and highlight it as a potential therapeutic target in COPD.
Keywords: Airway inflammation; Alveolar macrophages; COPD; Pro-inflammatory macrophage activation; RANKL.
背景：慢性气道炎症是慢性阻塞性肺疾病（COPD）发病及进展的关键驱动因素。肺泡巨噬细胞（AMs）的活化状态以及炎性细胞因子释放是该过程中的关键表型特征。尽管RANKL已被证实参与免疫调控及细胞因子分泌，但其在AMs促炎性激活中的具体作用，以及与COPD气道炎症的关联，尚不明确。本研究旨在探讨COPD中的RANKL通路，并阐明其在激活AM和气道炎症中的作用。
方法：首先，作者在肺组织中定量并定位RANKL及其受体RANK，同时评估COPD患者、吸烟者及非吸烟者的支气管肺泡灌洗液中CD86相关的促炎性巨噬细胞激活水平。随后，将野生型小鼠暴露于空气或香烟烟雾（CS）24周。在暴露于CS小鼠中，腹腔注射抗小鼠RANKL单克隆抗体或大鼠IgG2a kappa同型对照抗体，进一步评估巨噬细胞激活情况及气道炎症水平。最后，在体外实验中探讨RANKL在CS诱导的促炎性巨噬细胞激活及气道炎症中的生物学功能。
结果：研究发现，在COPD患者肺组织中，RANKL及RANK表达水平升高，同时CD86相关的促炎性巨噬细胞激活增强。RANKL及RANK主要定位于AMs。CS暴露显著增强小鼠的促炎性巨噬细胞激活及气道炎症，而使用抗RANKL单克隆抗体可减轻这些影响。在体外实验中，香烟烟雾提取物（CSE）上调AMs中RANKL及RANK的表达。AMs在RANKL或CSE刺激下呈促炎性活化状态，且细胞因子表达增加。此外，中和抗RANKL单克隆抗体可部分抑制CSE诱导的促炎性巨噬细胞激活及细胞因子表达。
结论：RANKL通过促炎性肺泡巨噬细胞激活参与COPD气道炎症。本研究加深了对RANKL通路在气道炎症中作用的认识，并提示RANKL可能成为COPD的潜在治疗靶点。
关键词：气道炎症；肺泡巨噬细胞；COPD；促炎性巨噬细胞激活；RANKL
（南方医科大学南方医院 倪钰 凌嘉骏 赵海金）
(Lu Zhou,Baiquan Zhang et al. RANKL promotes airway inflammation via pro-inflammatory alveolar macrophage activation in COPD. Respir Res. 2026 Jan 27;27(1):85. doi: 10.1186/s12931-026-03530-8.)
Abstract(Lu Zhou,Baiquan Zhang et al. RANKL promotes airway inflammation via pro-inflammatory alveolar macrophage activation in COPD. Respir Res. 2026 Jan 27;27(1):85. doi: 10.1186/s12931-026-03530-8.)
Background: Chronic airway inflammation is a key mechanism involved in the pathogenesis and progression of chronic obstructive pulmonary disease (COPD). Altered activation states of alveolar macrophages (AMs) and the release of inflammatory cytokines represent critical phenotypes in this inflammatory process. Although RANKL is known to participate in immune regulation and cytokine secretion, its potential involvement in pro-inflammatory activation of AMs and the associated contribution to airway inflammation in COPD remains incompletely understood. The purpose of this study is to investigate the RANKL pathway in COPD and to elucidate its role in AM activation and airway inflammation.
Methods: First, we quantified and localized RANKL and its receptor RANK in lung tissues and assessed CD86-associated pro-inflammatory macrophage activation in bronchoalveolar lavage fluid from COPD patients, smokers, and non-smokers. Next, wild-type mice were exposed to either air or cigarette smoke (CS) for 24 weeks. CS-exposed mice received intraperitoneal injections of either an anti-mouse RANKL monoclonal antibody or a rat IgG2a kappa isotype control antibody; macrophage activation status and airway inflammation were subsequently evaluated. Finally, we investigated the in vitro biological function of RANKL in CS-induced pro-inflammatory macrophage activation and airway inflammation.
Results: We found that the expression of both RANKL and RANK, along with enhanced CD86-associated pro-inflammatory macrophage activation, was increased in the lung tissues of COPD patients. In these tissues, RANKL and RANK were localized to AMs. In CS-exposed mice, pro-inflammatory macrophage activation and airway inflammation were significantly increased; however, these effects were ameliorated in CS-exposed mice treated with the anti-RANKL monoclonal antibody. In vitro, cigarette smoke extract (CSE) up-regulated the expression of RANKL and RANK in AMs. AMs responded to CSE and RANKL stimulation by exhibiting pro-inflammatory activation and enhanced cytokine expression. Furthermore, CSE-induced pro-inflammatory macrophage activation and cytokine expression were partially inhibited by the addition of a neutralizing anti-RANKL monoclonal antibody.
Conclusion: RANKL contributes to airway inflammation through pro-inflammatory alveolar macrophage activation in COPD. These findings extend current understanding of the role of the RANKL pathway in airway inflammation and highlight it as a potential therapeutic target in COPD.
Keywords: Airway inflammation; Alveolar macrophages; COPD; Pro-inflammatory macrophage activation; RANKL.
(倪钰 凌嘉骏 赵海金)
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