Sputum transcriptomics reveal up-regulation of IL-1 receptor family members in severe asthma

Publication date: Available online 18 May 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Christos Rossios, Stelios Pavlidis, Uruj Hoda, Chih-Hsi Kuo, Coen Wiegman, Kirsty Russell, Kai Sun, Matthew J. Loza, Frederic Baribaud, Andrew L. Durham, Oluwaseun Ojo, Rene Lutter, Anthony Rowe, Aruna Bansal, Charles Auffray, Ana Sousa, Julie Corfield, Ratko Djukanovic, Yike Guo, Peter J. Sterk, Kian Fan Chung, Ian M. Adcock
BackgroundSputum analysis in asthma is used to define airway inflammatory processes and may guide therapy.ObjectiveTo determine differential gene and protein expression in sputum samples from patients with severe asthma (SA) compared to mild-moderate non-smoking asthmatics (MMA).MethodsInduced sputum was obtained from non-smoking SA (SAn), smokers/ex-smokers with SA (SAsm), MMA and healthy non-smoking controls. Differential cell counts, microarray analysis of cell pellets and SOMAscan analysis of sputum analytes was performed. CRID3 was used to inhibit the inflammasome in a mouse model of severe asthma.ResultsEosinophilic and mixed neutrophilic/eosinophilic inflammation were more prevalent in SA compared to MMA. 42 genes probes were up-regulated (>2-fold) in SAn compared to MMA including IL-1R family and NRLP3 inflammasome members (FDR<0.05). The inflammasome proteins NLRP1, NLRP3 and NLRC4 were associated with neutrophilic asthma and with sputum IL-1β protein whilst eosinophilic asthma was associated with an IL-13-induced Th2 signature and IL1RL1 mRNA expression. These differences were sputum-specific since no activation of NLRP3 or enrichment of IL-1R family genes in bronchial brushings or biopsies in SA was observed. Expression of NLRP3 and of the IL-1R family genes was validated in the Airway Disease Endotyping for Personalized Therapeutics (ADEPT) cohort. Inflammasome inhibition using CRID3 prevented airway hyperresponsiveness and airway inflammation (both neutrophilia and eosinophilia) in a mouse model of severe allergic asthma.ConclusionIL1RL1 gene expression is associated with eosinophilic SA whilst NLRP3 inflammasome expression is highest in neutrophilic SA. Th2-driven eosinophilic inflammation and neutrophil-associated inflammasome activation may represent interacting pathways in SA.

Teaser

The study shows the value of sputum transcriptomics for understanding severe asthma mechanisms and identifies different IL-1R family members with different inflammatory phenotypes. Suppressing the inflammasome attenuates Th2 and non-Th2 features in vivo.


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