重度、激素抵抗性哮喘中NLRP3炎性小体调节、IL-1β依赖的应答作用
2017/09/29
摘要
原理：重度、激素抵抗性哮喘是哮喘治疗中的难点。哮喘疾病的异质性及发病机制了解的匮乏使其治疗目标难以明确。NLRP3炎性小体在COPD、气道感染及中性粒细胞性哮喘中过度表达，IL-1β也相应地过度表达。然而，其在发病机制中的作用及潜在的治疗靶点仍不甚明了，在重度、激素抵抗型哮喘中地作用也不清楚。
目的：探究NLRP3炎性小体及IL-1β在重度、激素抵抗型哮喘中的作用及治疗靶点。
方法:我们制作了有衣原体、嗜血杆菌感染，卵蛋白诱导的重度、激素抵抗型过敏性气道疾病的小鼠模型。这些模型具备了人类疾病所呈现的一些标志，包括气道中性粒细胞升高，NLRP3炎性小体、IL-1β表达。NLRP3炎性小体、IL-1β表达在重度、激素抵抗型哮喘中的作用及潜在靶点的检测应用了高选择性NLRP3抑制剂MCC950，特异性caspase-1抑制剂Ac-YVAD-cho和中和抗IL-1β抗体。IL-1β诱导的中性粒细胞性感染检测使用了IL-1β和抗Ly6G抗体。
检测与主要结果：衣原体、嗜血杆菌感染促进NLRP3, caspase-1, IL-1β表达从而促进激素抵抗的中性粒细胞性感染和气道高反应。哮喘中性粒细胞性气道感染、疾病严重性和激素抵抗与NLRP3和IL-1β表达有关。抗IL-1β抗体, AcYVAD-cho和MCC950治疗后抑制IL-1β表达及小鼠的激素抵抗的表型，而IL-1β可调控这些表型。中性粒细胞减少抑制IL-1β诱导的激素抵抗型气道高反应。
结论：NLRP3炎性小体表达促进了激素抵抗型哮喘，是疾病的潜在治疗靶点。
Role for NLRP3 inflammasome-mediated, IL-1β-dependent responses in severe, steroid-resistant asthma.
Richard Y. Kim, James W. Pinkerton, Ama T. Essilfie, Avril A. B. Robertson, Katherine J. Baines, Alexandra C. Brown, Jemma R. Mayall, Md. Khadem Ali, Malcolm R. Starkey, Nicole G. Hansbro, Jeremy A. Hirota, Lisa G. Wood, Jodie L. Simpson, Darryl A. Knight, Peter A. Wark, Peter G. Gibson, Luke A. J. O’Neill, Matthew A. Cooper, Jay C. Horvat, Philip M. Hansbro.
Abstract
RATIONALE:Severe, steroid-resistant asthma is the major unmet need in asthma therapy. Disease heterogeneity and poor understanding of pathogenic mechanisms hampers the identification of therapeutic targets. Excessive NLRP3 inflammasome and concomitant IL-1β responses occur in COPD, respiratory infections and neutrophilic asthma. However, the direct contributions to pathogenesis, mechanisms involved and potential for therapeutic targeting remain poorly understood, and are unknown in severe, steroid-resistant asthma.
OBJECTIVES:To investigate the roles and therapeutic targeting of the NLRP3 inflammasome and IL-1β in severe, steroid-resistant asthma.
METHODS:We developed mouse models of Chlamydia, and Haemophilus, respiratory infection-mediated, ovalbumin-induced severe, steroid-resistant allergic airways disease. These models share the hallmark features of human disease, including elevated airway neutrophils, and NLRP3 inflammasome and IL-1β responses. The roles and potential for targeting of NLRP3 inflammasome, caspase-1, and IL-1β responses in experimental severe, steroid-resistant asthma were examined using a highly-selective NLRP3 inhibitor, MCC950, the specific caspase-1 inhibitor, Ac-YVAD-cho, and neutralizing anti-IL-1β antibody. Roles for IL-1β-induced neutrophilic inflammation were examined using IL-1β and anti-Ly6G.
MEASUREMENTS AND MAIN RESULTS:Chlamydia and Haemophilus infections increase NLRP3, caspase-1, IL-1β responses that drive steroid-resistant neutrophilic inflammation and airways hyper-responsiveness. Neutrophilic airway inflammation, disease severity and steroid-resistance in human asthma correlates with NLRP3 and IL-1β expression. Treatment with anti-IL-1β, AcYVAD-cho, and MCC950 suppressed IL-1β responses and the important steroid-resistant features of disease in mice, whereas IL-1β administration recapitulated these features. Neutrophil depletion suppressed IL-1β-induced steroid-resistant airways hyper-responsiveness.
CONCLUSIONS:NLRP3 inflammasome responses drive experimental severe, steroid-resistant asthma and are potential therapeutic targets in this disease.
原理：重度、激素抵抗性哮喘是哮喘治疗中的难点。哮喘疾病的异质性及发病机制了解的匮乏使其治疗目标难以明确。NLRP3炎性小体在COPD、气道感染及中性粒细胞性哮喘中过度表达，IL-1β也相应地过度表达。然而，其在发病机制中的作用及潜在的治疗靶点仍不甚明了，在重度、激素抵抗型哮喘中地作用也不清楚。
目的：探究NLRP3炎性小体及IL-1β在重度、激素抵抗型哮喘中的作用及治疗靶点。
方法:我们制作了有衣原体、嗜血杆菌感染，卵蛋白诱导的重度、激素抵抗型过敏性气道疾病的小鼠模型。这些模型具备了人类疾病所呈现的一些标志，包括气道中性粒细胞升高，NLRP3炎性小体、IL-1β表达。NLRP3炎性小体、IL-1β表达在重度、激素抵抗型哮喘中的作用及潜在靶点的检测应用了高选择性NLRP3抑制剂MCC950，特异性caspase-1抑制剂Ac-YVAD-cho和中和抗IL-1β抗体。IL-1β诱导的中性粒细胞性感染检测使用了IL-1β和抗Ly6G抗体。
检测与主要结果：衣原体、嗜血杆菌感染促进NLRP3, caspase-1, IL-1β表达从而促进激素抵抗的中性粒细胞性感染和气道高反应。哮喘中性粒细胞性气道感染、疾病严重性和激素抵抗与NLRP3和IL-1β表达有关。抗IL-1β抗体, AcYVAD-cho和MCC950治疗后抑制IL-1β表达及小鼠的激素抵抗的表型，而IL-1β可调控这些表型。中性粒细胞减少抑制IL-1β诱导的激素抵抗型气道高反应。
结论：NLRP3炎性小体表达促进了激素抵抗型哮喘，是疾病的潜在治疗靶点。
(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)
(Am J Respir Crit Care Med. 2017 Aug 1;196(3):283-297. doi: 10.1164/rccm.201609-1830OC.)
(Am J Respir Crit Care Med. 2017 Aug 1;196(3):283-297. doi: 10.1164/rccm.201609-1830OC.)
Role for NLRP3 inflammasome-mediated, IL-1β-dependent responses in severe, steroid-resistant asthma.
Richard Y. Kim, James W. Pinkerton, Ama T. Essilfie, Avril A. B. Robertson, Katherine J. Baines, Alexandra C. Brown, Jemma R. Mayall, Md. Khadem Ali, Malcolm R. Starkey, Nicole G. Hansbro, Jeremy A. Hirota, Lisa G. Wood, Jodie L. Simpson, Darryl A. Knight, Peter A. Wark, Peter G. Gibson, Luke A. J. O’Neill, Matthew A. Cooper, Jay C. Horvat, Philip M. Hansbro.
Abstract
RATIONALE:Severe, steroid-resistant asthma is the major unmet need in asthma therapy. Disease heterogeneity and poor understanding of pathogenic mechanisms hampers the identification of therapeutic targets. Excessive NLRP3 inflammasome and concomitant IL-1β responses occur in COPD, respiratory infections and neutrophilic asthma. However, the direct contributions to pathogenesis, mechanisms involved and potential for therapeutic targeting remain poorly understood, and are unknown in severe, steroid-resistant asthma.
OBJECTIVES:To investigate the roles and therapeutic targeting of the NLRP3 inflammasome and IL-1β in severe, steroid-resistant asthma.
METHODS:We developed mouse models of Chlamydia, and Haemophilus, respiratory infection-mediated, ovalbumin-induced severe, steroid-resistant allergic airways disease. These models share the hallmark features of human disease, including elevated airway neutrophils, and NLRP3 inflammasome and IL-1β responses. The roles and potential for targeting of NLRP3 inflammasome, caspase-1, and IL-1β responses in experimental severe, steroid-resistant asthma were examined using a highly-selective NLRP3 inhibitor, MCC950, the specific caspase-1 inhibitor, Ac-YVAD-cho, and neutralizing anti-IL-1β antibody. Roles for IL-1β-induced neutrophilic inflammation were examined using IL-1β and anti-Ly6G.
MEASUREMENTS AND MAIN RESULTS:Chlamydia and Haemophilus infections increase NLRP3, caspase-1, IL-1β responses that drive steroid-resistant neutrophilic inflammation and airways hyper-responsiveness. Neutrophilic airway inflammation, disease severity and steroid-resistance in human asthma correlates with NLRP3 and IL-1β expression. Treatment with anti-IL-1β, AcYVAD-cho, and MCC950 suppressed IL-1β responses and the important steroid-resistant features of disease in mice, whereas IL-1β administration recapitulated these features. Neutrophil depletion suppressed IL-1β-induced steroid-resistant airways hyper-responsiveness.
CONCLUSIONS:NLRP3 inflammasome responses drive experimental severe, steroid-resistant asthma and are potential therapeutic targets in this disease.
上一篇：
IL-22在室内尘螨诱导模型中促进Reg3γ表达抑制过敏性炎症反应
下一篇：
MUC5AC和MUC5B糖型改变急性哮喘儿童患者的黏蛋白合成
