局部受体相互作用蛋白激酶2抑制减轻HDM诱导的哮喘
2024/08/28
摘要
屋尘螨（HDM）是过敏性哮喘最常见的诱因，先天性和适应性免疫机制在结果中起着至关重要的作用。我们最近发现NOD1/RIPK2信号通路是小鼠HDM诱导哮喘的相关因素。本研究旨在评估在携带哮喘相关风险等位基因的野生型（WT）和人源化（h）NOD1小鼠中，使用HDM诱导的哮喘模型，局部施用药理学RIPK2抑制剂作为预防和治疗方法的有效性，以及使用哮喘患者的气道液体界面（ALI）上皮培养物的相关性。在小鼠HDM诱导的哮喘模型中，通过鼻内注射RIPK2抑制剂进行预防或治疗。评估气道高反应性（AHR）、支气管肺泡灌洗液成分、细胞因子/趋化因子表达和粘液产生，以及抑制剂对精确切割肺切片（PCLS）的影响。此外，对哮喘患者和对照组的ALI培养物进行了抑制剂测试。虽然RIPK2抑制剂的局部预防性给药降低了WT小鼠的AHR、嗜酸性粒细胞增多、粘液产生、Th2细胞因子和IL-33，但其治疗性给药未能降低上述参数，IL-33除外。相比之下，治疗性RIPK2抑制减轻了hNOD1小鼠的所有哮喘特征。PCLS的结果强调了TSLP和IL-33在HDM的NOD1依赖性反应中的早期作用，以及NOD1信号传导对IL-13效应器反应的晚期作用。RIPK2抑制剂下调哮喘患者HDM刺激的ALI上皮培养物中的TSLP和趋化因子。这些数据支持通过RIPK2抑制NOD1信号通路的局部干扰可能代表HDM诱导的哮喘的一种新的治疗方法。
Local Receptor-interacting Protein Kinase 2 inhibition mitigates HDM-induced asthma
Daniel Alvarez-Simon, Saliha Ait Yahia, Camille Audousset, Martine Fanton d'Andon, Mathias Chamaillard, Ivo Gomperts Boneca, Anne Tsicopoulos
Abstract
House dust mite (HDM) is the most frequent trigger of allergic asthma with innate and adaptive immune mechanisms playing critical roles in outcomes. We recently identified the NOD1/RIPK2 signalling pathway as a relevant contributor to murine HDM-induced asthma. This study aimed to evaluate the effectiveness of a pharmacological RIPK2 inhibitor administered locally as a preventive and therapeutic approach using an HDM-induced asthma model in Wild-type (WT) and humanized (h)NOD1 mice harbouring an asthma associated risk allele, and its relevance using airway liquid interface (ALI) epithelial cultures from asthmatics. A RIPK2 inhibitor was administered intra-nasally either preventively or therapeutically in a murine HDM-induced asthma model. Airway hyperresponsiveness (AHR), bronchoalveolar lavage composition, cytokine/chemokines expression and mucus production were evaluated, as well as the effect of the inhibitor on precision-cut lung slices (PCLS). Furthermore, the inhibitor was tested on ALI cultures from asthmatics and controls. While local preventive administration of the RIPK2 inhibitor reduced AHR, eosinophilia, mucus production, Th2 cytokines and IL-33 in WT mice, its therapeutic administration failed to reduce the above parameters, except IL-33. By contrast, therapeutic RIPK2 inhibition mitigated all asthma features in hNOD1 mice. Results of PCLS emphasized an early role of TSLP and IL-33 in the NOD1-dependent response to HDM, and a late effect of NOD1 signalling on IL-13 effector response. RIPK2 inhibitor down-regulated TSLP and chemokines in HDM-stimulated ALI epithelial cultures from asthma patients. These data support that local interference of the NOD1 signalling pathway through RIPK2 inhibition may represent a new therapeutic approach in HDM-induced asthma.
屋尘螨（HDM）是过敏性哮喘最常见的诱因，先天性和适应性免疫机制在结果中起着至关重要的作用。我们最近发现NOD1/RIPK2信号通路是小鼠HDM诱导哮喘的相关因素。本研究旨在评估在携带哮喘相关风险等位基因的野生型（WT）和人源化（h）NOD1小鼠中，使用HDM诱导的哮喘模型，局部施用药理学RIPK2抑制剂作为预防和治疗方法的有效性，以及使用哮喘患者的气道液体界面（ALI）上皮培养物的相关性。在小鼠HDM诱导的哮喘模型中，通过鼻内注射RIPK2抑制剂进行预防或治疗。评估气道高反应性（AHR）、支气管肺泡灌洗液成分、细胞因子/趋化因子表达和粘液产生，以及抑制剂对精确切割肺切片（PCLS）的影响。此外，对哮喘患者和对照组的ALI培养物进行了抑制剂测试。虽然RIPK2抑制剂的局部预防性给药降低了WT小鼠的AHR、嗜酸性粒细胞增多、粘液产生、Th2细胞因子和IL-33，但其治疗性给药未能降低上述参数，IL-33除外。相比之下，治疗性RIPK2抑制减轻了hNOD1小鼠的所有哮喘特征。PCLS的结果强调了TSLP和IL-33在HDM的NOD1依赖性反应中的早期作用，以及NOD1信号传导对IL-13效应器反应的晚期作用。RIPK2抑制剂下调哮喘患者HDM刺激的ALI上皮培养物中的TSLP和趋化因子。这些数据支持通过RIPK2抑制NOD1信号通路的局部干扰可能代表HDM诱导的哮喘的一种新的治疗方法。
(中日友好医院呼吸与危重症医学科 李红雯 摘译 林江涛 审校)
(Eur Respir J. 2024 Aug 8:2302288. doi: 10.1183/13993003.02288-2023.)
(Eur Respir J. 2024 Aug 8:2302288. doi: 10.1183/13993003.02288-2023.)
Local Receptor-interacting Protein Kinase 2 inhibition mitigates HDM-induced asthma
Daniel Alvarez-Simon, Saliha Ait Yahia, Camille Audousset, Martine Fanton d'Andon, Mathias Chamaillard, Ivo Gomperts Boneca, Anne Tsicopoulos
Abstract
House dust mite (HDM) is the most frequent trigger of allergic asthma with innate and adaptive immune mechanisms playing critical roles in outcomes. We recently identified the NOD1/RIPK2 signalling pathway as a relevant contributor to murine HDM-induced asthma. This study aimed to evaluate the effectiveness of a pharmacological RIPK2 inhibitor administered locally as a preventive and therapeutic approach using an HDM-induced asthma model in Wild-type (WT) and humanized (h)NOD1 mice harbouring an asthma associated risk allele, and its relevance using airway liquid interface (ALI) epithelial cultures from asthmatics. A RIPK2 inhibitor was administered intra-nasally either preventively or therapeutically in a murine HDM-induced asthma model. Airway hyperresponsiveness (AHR), bronchoalveolar lavage composition, cytokine/chemokines expression and mucus production were evaluated, as well as the effect of the inhibitor on precision-cut lung slices (PCLS). Furthermore, the inhibitor was tested on ALI cultures from asthmatics and controls. While local preventive administration of the RIPK2 inhibitor reduced AHR, eosinophilia, mucus production, Th2 cytokines and IL-33 in WT mice, its therapeutic administration failed to reduce the above parameters, except IL-33. By contrast, therapeutic RIPK2 inhibition mitigated all asthma features in hNOD1 mice. Results of PCLS emphasized an early role of TSLP and IL-33 in the NOD1-dependent response to HDM, and a late effect of NOD1 signalling on IL-13 effector response. RIPK2 inhibitor down-regulated TSLP and chemokines in HDM-stimulated ALI epithelial cultures from asthma patients. These data support that local interference of the NOD1 signalling pathway through RIPK2 inhibition may represent a new therapeutic approach in HDM-induced asthma.
上一篇：
白细胞介素-2 家族细胞因子 IL-9 和 IL-21 对哮喘的先天性和适应性 2 型免疫有不同的调节作用
下一篇：
哮喘多基因风险评分的表观基因组划分揭示不同基因驱动疾病的通路
