Bronchial epithelial cell transcriptome shows endotype heterogeneity of asthma in patients with NSAID-exacerbated respiratory disease

• Published in: Journal of allergy and clinical immunology Vol. 151; no. 4; pp. 953 - 965
• Main Authors: Jakiela, Bogdan, Soja, Jerzy, Sladek, Krzysztof, Przybyszowski, Marek, Plutecka, Hanna, Gielicz, Anna, Licholai, Sabina, Aab, Alar, Rebane, Ana, Bochenek, Grazyna
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.04.2023
• Subjects: Anti-Inflammatory Agents, Non-Steroidal - adverse effects; Asthma; Asthma - genetics; asthma endotypes; bronchial epithelium; Epithelial Cells; gene expression; Humans; Interleukin-17 - genetics; NSAID–exacerbated respiratory disease; Respiration Disorders; Respiratory Tract Diseases; Transcriptome; cysLTs; asthma endotypes; NSAID–exacerbated respiratory disease; BALF; DEG; HBECs; Asthma; NSAIDs; N-ERD; PNEC; NTA; qPCR; bronchial epithelium; gene expression; T2
• ISSN: 0091-6749; 1097-6825; 1085-8725; 1097-6825
• DOI: 10.1016/j.jaci.2022.10.029

Nonsteroidal anti-inflammatory drugs–exacerbated respiratory disease (N-ERD) is currently classified as a type-2 (T2) immune-mediated disease characterized by asthma, chronic rhinosinusitis, and hypersensitivity to cyclooxygenase-1 inhibitors. The aim of this study was to characterize immunological endotypes of N-ERD based on the gene expression profile in the bronchial epithelium. mRNA transcriptome (mRNA-sequencing) was analyzed in bronchial brushings from patients with N-ERD (n = 22), those with nonsteroidal anti-inflammatory drug–tolerant asthma (NTA, n = 21), and control subjects (n = 11). Additionally, lipid and protein mediators were measured in bronchoalveolar lavage fluid (BALF). Initial analysis of the entire asthma group revealed 2 distinct gene expression signatures: “T2-high” with increased expression of T2-related genes (eg, CLCA1, CST1), and “proinflammatory” characterized by the expression of innate immunity (eg, FOSB, EGR3) and IL-17A response genes. These endotypes showed similar prevalence in N-ERD and NTA (eg, T2-high: 33% and 32%, respectively). T2-high asthma was characterized by increased expression of mast cell and eosinophil markers, goblet cell hyperplasia, and elevated LTE4 and PGD2 in BALF. Patients with a proinflammatory endotype showed mainly neutrophilic inflammation and increased innate immunity mediators in BALF. Furthermore, the proinflammatory signature was associated with a more severe course of asthma and marked airway obstruction. These signatures could be recreated in vitro by exposure of bronchial epithelial cells to IL-13 (T2-high) and IL-17A (proinflammatory). T2-high signature was found only in one-third of patients with N-ERD, which was similar to what was found in patients with NTA. The proinflammatory endotype, which also occurred in N-ERD, suggests a novel mechanism of severe disease developing on a non-T2 background.