1 Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia.
2 Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
Am J Respir Crit Care Med. 2017 Aug 1;196(3):283-297. doi: 10.1164/rccm.201609-1830OC.
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 nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome and concomitant IL-1β responses occur in chronic obstructive pulmonary disease, 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.
To investigate the roles and therapeutic targeting of the NLRP3 inflammasome and IL-1β in severe, steroid-resistant asthma.
We developed mouse models of Chlamydia and Haemophilus respiratory infection-mediated, ovalbumin-induced severe, steroid-resistant allergic airway 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.
Chlamydia and Haemophilus infections increase NLRP3, caspase-1, IL-1β responses that drive steroid-resistant neutrophilic inflammation and airway hyperresponsiveness. Neutrophilic airway inflammation, disease severity, and steroid resistance in human asthma correlate with NLRP3 and IL-1β expression. Treatment with anti-IL-1β, Ac-YVAD-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 airway hyperresponsiveness.
NLRP3 inflammasome responses drive experimental severe, steroid-resistant asthma and are potential therapeutic targets in this disease.
严重的、类固醇耐药的哮喘是哮喘治疗中未满足的主要需求。疾病异质性和对发病机制的理解不足阻碍了治疗靶点的确定。NLRP3 炎性小体和伴随的白细胞介素 1β（IL-1β）反应在慢性阻塞性肺疾病、呼吸道感染和中性粒细胞性哮喘中过度发生。然而，其对发病机制的直接贡献、涉及的机制以及潜在的治疗靶点仍知之甚少，在严重的、类固醇耐药的哮喘中也尚不清楚。
研究 NLRP3 炎性小体和 IL-1β 在严重的、类固醇耐药性哮喘中的作用和治疗靶点。
我们建立了衣原体和嗜血杆菌呼吸道感染介导的、卵清蛋白诱导的严重的、类固醇耐药性变应性气道疾病的小鼠模型。这些模型具有人类疾病的标志性特征，包括气道嗜中性粒细胞升高以及 NLRP3 炎性小体和 IL-1β 反应。使用高度选择性的 NLRP3 抑制剂 MCC950、特异性 caspase-1 抑制剂 Ac-YVAD-cho 和中和抗 IL-1β 抗体，研究 NLRP3 炎性小体、半胱天冬酶-1 和 IL-1β 反应在实验性严重的、类固醇耐药性哮喘中的作用和潜在靶向作用。使用 IL-1β 和抗 Ly6G 研究了 IL-1β 诱导的嗜中性粒细胞炎症的作用。
衣原体和嗜血杆菌感染增加了 NLRP3、半胱天冬酶-1 和 IL-1β 反应，这些反应驱动了类固醇耐药性的嗜中性粒细胞炎症和气道高反应性。人类哮喘中的气道嗜中性粒细胞炎症、疾病严重程度和类固醇耐药性与 NLRP3 和 IL-1β 的表达相关。抗 IL-1β、Ac-YVAD-cho 和 MCC950 的治疗抑制了 IL-1β 反应和小鼠疾病的重要类固醇耐药特征，而 IL-1β 的给药再现了这些特征。嗜中性粒细胞耗竭抑制了 IL-1β 诱导的类固醇耐药性气道高反应性。
NLRP3 炎性小体反应驱动实验性严重的、类固醇耐药性哮喘，并且是该疾病的潜在治疗靶点。
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