Sputum transcriptomics reveal upregulation of IL-1 receptor family members in patients with severe asthma
Sputum transcriptomics reveal upregulation of IL-1 receptor family members in patients with severe asthma
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DOI：
10.1016/j.jaci.2017.02.045
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发表时间：
2018-02-01
影响因子：
14.2
通讯作者：
Adcock, Ian M.
中科院分区：
文献类型：
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作者：
Rossios, Christos;Pavlidis, Stelios;Adcock, Ian M.
背景资料：哮喘患者的痰液分析用于确定气道炎症过程，并可能指导治疗。目的：我们试图确定重度哮喘（SA）患者与非吸烟轻度/中度哮喘患者痰液样本中差异基因和蛋白质表达。方法：从患有SA的非吸烟患者、患有重度哮喘的吸烟者/戒烟者、患有轻度/中度哮喘（MMAs）的非吸烟患者、和健康的非吸烟对照受试者。进行细胞分类计数、细胞团的微阵列分析和痰液分析物的SOMAscan分析。CRID 3用于抑制SA小鼠模型中的炎性小体。结果：与MMAs相比，SA患者中嗜酸性粒细胞和混合嗜酸性粒细胞/嗜酸性粒细胞炎症更普遍。42个基因探针在不吸烟的重度哮喘患者中表达上调（> 2倍），包括IL-1受体（IL-1 R）家族和核苷酸结合寡聚化结构域、富含亮氨酸重复序列和含吡啉结构域3（NRLP 3）炎性小体成员（假发现率< 0.05）。炎性体蛋白核苷酸结合寡聚化结构域、富含亮氨酸的重复序列和含有1的pyrin结构域（NLRP 1）、NLRP 3和核苷酸结合寡聚化结构域（NOD）样受体C4（NLRC 4）与嗜中性粒细胞哮喘和痰液IL-1 β蛋白水平相关，而嗜酸性粒细胞性哮喘与IL-13诱导的T-H（2）信号和IL-1受体样1（IL 1 RL 1）mRNA表达有关。这些差异是痰液特异性的，因为在SA患者的支气管刷检或活检标本中未观察到NLRP 3活化或IL-1 R家族基因富集。NLRP 3和IL-1 R家族基因的表达在个性化治疗的气道疾病内分型队列中得到验证。结论：IL 1 RL 1基因表达与嗜酸性粒细胞SA相关，而NLRP 3炎性体表达在嗜酸性粒细胞SA患者中最高。T-H（2）驱动的嗜酸性粒细胞炎症和嗜酸性粒细胞相关炎性小体激活可能代表SA患者的相互作用途径。
Background: Sputum analysis in asthmatic patients is used to define airway inflammatory processes and might guide therapy.Objective: We sought to determine differential gene and protein expression in sputum samples from patients with severe asthma (SA) compared with nonsmoking patients with mild/moderate asthma.Methods: Induced sputum was obtained from nonsmoking patients with SA, smokers/ex-smokers with severe asthma, nonsmoking patients with mild/moderate asthma (MMAs), and healthy nonsmoking control subjects. Differential cell counts, microarray analysis of cell pellets, and SOMAscan analysis of sputum analytes were performed. CRID3 was used to inhibit the inflammasome in a mouse model of SA.Results: Eosinophilic and mixed neutrophilic/eosinophilic inflammation were more prevalent in patients with SA compared with MMAs. Forty-two genes probes were upregulated (> 2-fold) in nonsmoking patients with severe asthma compared with MMAs, including IL-1 receptor (IL-1R) family and nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain containing 3 (NRLP3) inflammasome members (false discovery rate < 0.05). The inflammasome proteins nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain containing 1 (NLRP1), NLRP3, and nucleotide-binding oligomerization domain (NOD)-like receptor C4 (NLRC4) were associated with neutrophilic asthma and with sputum IL-1 beta protein levels, whereas eosinophilic asthma was associated with an IL-13-induced T-H(2) signature and IL-1 receptor-like 1 (IL1RL1) mRNA expression. These differences were sputum specific because no activation of NLRP3 or enrichment of IL-1R family genes in bronchial brushings or biopsy specimens in patients with SA was observed. Expression of NLRP3 and of the IL-1R family genes was validated in the Airway Disease Endotyping for Personalized Therapeutics cohort. Inflammasome inhibition using CRID3 prevented airway hyperresponsiveness and airway inflammation (both neutrophilia and eosinophilia) in a mouse model of severe allergic asthma.Conclusion: IL1RL1 gene expression is associated with eosinophilic SA, whereas NLRP3 inflammasome expression is highest in patients with neutrophilic SA. T-H(2)-driven eosinophilic inflammation and neutrophil-associated inflammasome activation might represent interacting pathways in patients with SA.