Sputum transcriptomics reveal upregulation of IL-1 receptor family members in patients with severe asthma

• Published in: Journal of allergy and clinical immunology Vol. 141; no. 2; pp. 560 - 570
• Main Authors: Rossios, Christos, Pavlidis, Stelios, Hoda, Uruj, Kuo, Chih-Hsi, Wiegman, Coen, Russell, Kirsty, Sun, Kai, Loza, Matthew J., Baribaud, Frederic, Durham, Andrew L., Ojo, Oluwaseun, Lutter, Rene, Rowe, Anthony, Bansal, Aruna, Auffray, Charles, Sousa, Ana, Corfield, Julie, Djukanovic, Ratko, Guo, Yike, Sterk, Peter J., Chung, Kian Fan, Adcock, Ian M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.02.2018; Elsevier Limited
• Subjects: Adult; Allergies; Allergy and Immunology; Animals; Asthma; Asthma - immunology; Asthma - pathology; Biomarkers; Biopsy; C-reactive protein; Cell activation; Data analysis; DNA microarrays; eosinophil; Eosinophilia; Eosinophils - immunology; Eosinophils - pathology; exhaled nitric oxide; Female; Gene expression; Gene Expression Profiling; Humans; IL-1α; IL-1β; IL-33 receptor; inflammasome; Inflammasomes; Inflammation; Interleukin 1; Interleukin 1 receptors; Interleukin 13; Leucine; Leukocytes (eosinophilic); Leukocytes (neutrophilic); Lymphocytes T; Male; Mice; Middle Aged; neutrophil; Neutrophilia; Neutrophils; Neutrophils - immunology; Neutrophils - pathology; Oligomerization; Pyrin protein; Receptors, Interleukin-1 - immunology; Respiratory tract diseases; Severe asthma; Software; Sputum; Sputum - immunology; TH2; Th2 Cells - immunology; Th2 Cells - pathology; Up-Regulation - immunology; Feno; C-reactive protein; AHR; NLRC4; IL-1R; neutrophil; SA; SAsm; HDM; IL1RL1; IL18RAP; FDR; exhaled nitric oxide; NLRP3; Severe asthma; NLRP1; eosinophil; RT-qPCR; MMA; SAn; NOD; U-BIOPRED; IRAK3; IL-1β; IL-1α; BAL; ES; ADEPT; inflammasome; GSVA; IL-33 receptor; IL18R1; TH2; Unbiased Biomarkers for the Prediction of Respiratory Diseases Outcomes; IL-1 receptor; T H2; Enrichment score; Nonsmoking patients with severe asthma; IL-18 receptor 1; Airway hyperresponsiveness; IL-18 receptor accessory protein; Nucleotide-binding oligomerization domain (NOD)-like receptor C4; Quantitative RT-PCR; IL-1 receptor–like 1; Fraction of exhaled nitric oxide; Smokers and ex-smokers with severe asthma; Bronchoalveolar lavage; Nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain containing 1; Airway Disease Endotyping for Personalized Therapeutics; Nonsmoking patient with mild/moderate asthma; F eno; House dust mite; nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain containing 3; Gene set variation analysis; Nucleotide-binding oligomerization domain; False discovery rate; IL-1 receptor–associated kinase 3; T(H)2
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2017.02.045

Sputum analysis in asthmatic patients is used to define airway inflammatory processes and might guide therapy. 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. 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. 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-1β protein levels, whereas eosinophilic asthma was associated with an IL-13–induced TH2 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. IL1RL1 gene expression is associated with eosinophilic SA, whereas NLRP3 inflammasome expression is highest in patients with neutrophilic SA. TH2-driven eosinophilic inflammation and neutrophil-associated inflammasome activation might represent interacting pathways in patients with SA.