NLRP3炎性小体介导的IL-1β依赖性应答在重症激素抵抗性哮喘中的作用
2017/12/29
摘要
理由：哮喘治疗中尚不能满足的重大需求属于重症激素抵抗性哮喘。哮喘异质性及对重症激素抵抗性哮喘发病机制的认识不足阻碍了其治疗靶点的识别。在COPD、呼吸道感染与中性粒细胞性哮喘中，常常出现NLRP3炎性小体及其伴随的IL-1β应答过度表达。然而，它们对发病机制及潜在治疗靶点的直接贡献仍然知之甚少，并且在重症激素抵抗性哮喘中尚未可知。
目的：探讨NLRP3炎性小体和IL-1β在重症激素抵抗性哮喘中的作用及其治疗靶点。
方法：我们开发了一套使用衣原体或嗜血杆菌等呼吸道感染介导，由卵蛋白诱导的重症激素抵抗性过敏性气道疾病的小鼠模型。这些模型具有人类疾病的特征，包括升高的气道中性粒细胞，NLRP3炎性小体和IL-1β应答。采用高度选择性NLRP3抑制剂（MCC950）、特异性半胱氨酸蛋白酶-1抑制剂（Ac-YVAD-cho）以及中和抗IL-1β抗体，检测NLRP3炎性小体、半胱氨酸蛋白酶-1和IL-1β应答在实验性重症激素抵抗性哮喘中的作用和潜力。使用IL-1β和抗Ly6G抗体检测IL-1β在其诱导的中性粒细胞性炎症中的作用。
测量和主要结果：衣原体和嗜血杆菌感染增加了NLRP3、半胱氨酸蛋白酶-1、IL-1β应答，其驱动了激素抵抗中性粒细胞性炎症以及气道高反应性。在人类哮喘，中性粒细胞性气道炎症、疾病严重程度和激素抵抗与NLRP3及IL-1β表达相关。在小鼠模型中，用抗IL-1β抗体，AcYVAD-cho和MCC950治疗，抑制了IL-1β应答及该疾病重要的激素抵抗特征，而外源性注射IL-1β又重现了这些特征。中性粒细胞封闭抑制了IL-1β诱导的激素抵抗气道高反应性。
结论：NLRP3炎性小体驱动实验性重症激素抵抗性哮喘，它可能成为本病的潜在治疗靶点。
Role for NLRP3 inflammasome-mediated, IL-1β-dependent responses in severe, steroid-resistant asthma
Kim RY, Pinkerton JW, Essilfie AT, Robertson AAB, Baines KJ, Brown AC, Mayall JR, Ali MK, Starkey MR, Hansbro NG, Hirota JA, Wood LG, Simpson JL, Knight DA, Wark PA, Gibson PG, O'Neill LAJ, Cooper MA, Horvat JC, Hansbro PM.
Am J Respir Crit Care Med. 2017;196(3):283-297.
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.
理由：哮喘治疗中尚不能满足的重大需求属于重症激素抵抗性哮喘。哮喘异质性及对重症激素抵抗性哮喘发病机制的认识不足阻碍了其治疗靶点的识别。在COPD、呼吸道感染与中性粒细胞性哮喘中，常常出现NLRP3炎性小体及其伴随的IL-1β应答过度表达。然而，它们对发病机制及潜在治疗靶点的直接贡献仍然知之甚少，并且在重症激素抵抗性哮喘中尚未可知。
目的：探讨NLRP3炎性小体和IL-1β在重症激素抵抗性哮喘中的作用及其治疗靶点。
方法：我们开发了一套使用衣原体或嗜血杆菌等呼吸道感染介导，由卵蛋白诱导的重症激素抵抗性过敏性气道疾病的小鼠模型。这些模型具有人类疾病的特征，包括升高的气道中性粒细胞，NLRP3炎性小体和IL-1β应答。采用高度选择性NLRP3抑制剂（MCC950）、特异性半胱氨酸蛋白酶-1抑制剂（Ac-YVAD-cho）以及中和抗IL-1β抗体，检测NLRP3炎性小体、半胱氨酸蛋白酶-1和IL-1β应答在实验性重症激素抵抗性哮喘中的作用和潜力。使用IL-1β和抗Ly6G抗体检测IL-1β在其诱导的中性粒细胞性炎症中的作用。
测量和主要结果：衣原体和嗜血杆菌感染增加了NLRP3、半胱氨酸蛋白酶-1、IL-1β应答，其驱动了激素抵抗中性粒细胞性炎症以及气道高反应性。在人类哮喘，中性粒细胞性气道炎症、疾病严重程度和激素抵抗与NLRP3及IL-1β表达相关。在小鼠模型中，用抗IL-1β抗体，AcYVAD-cho和MCC950治疗，抑制了IL-1β应答及该疾病重要的激素抵抗特征，而外源性注射IL-1β又重现了这些特征。中性粒细胞封闭抑制了IL-1β诱导的激素抵抗气道高反应性。
结论：NLRP3炎性小体驱动实验性重症激素抵抗性哮喘，它可能成为本病的潜在治疗靶点。
(张红萍1 王刚 四川大学华西医院中西医结合科呼吸病组 610041 摘译)
（Am J Respir Crit Care Med. 2017;196(3):283-297.）
（Am J Respir Crit Care Med. 2017;196(3):283-297.）
Role for NLRP3 inflammasome-mediated, IL-1β-dependent responses in severe, steroid-resistant asthma
Kim RY, Pinkerton JW, Essilfie AT, Robertson AAB, Baines KJ, Brown AC, Mayall JR, Ali MK, Starkey MR, Hansbro NG, Hirota JA, Wood LG, Simpson JL, Knight DA, Wark PA, Gibson PG, O'Neill LAJ, Cooper MA, Horvat JC, Hansbro PM.
Am J Respir Crit Care Med. 2017;196(3):283-297.
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.
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