Transcriptomics of biopsies identifies novel genes and pathways linked to neutrophilic inflammation in severe asthma.

Abstract

Severe asthma is a complex disease. Transcriptomic profiling has contributed to understanding the pathogenesis of asthma, especially type-2 inflammation. However, there is still poor understanding of non-type-2 asthma, and consequently, there are limited treatment options. The aim of this study was to identify differentially expressed genes (DEGs) and pathways in endobronchial biopsies associated with inflammatory phenotypes of severe asthma. This cross-sectional study examined endobronchial biopsies from 47 adults with severe asthma (neutrophilic asthma (NA) n=9, eosinophilic asthma (EA) n=22 and paucigranulocytic asthma (PGA) n=16) and 13healthy controls (HC). RNA was extracted and transcriptomic profiles generated (Illumina Humanref-12V4) and analysed using GeneSpring GX14.9.1. Pathway identification using Ingenuity Pathway Analysis. NA had the most distinct profile, with signature of 60 top-ranked DEGs (FC >±2) including genes associated with innate immunity response, neutrophil degranulation and IL-10signalling. NA presented enrichment to pathways previously linked to neutrophilic inflammation; dendritic cell maturation, Th1, TREM1, inflammasome, Th17 and p38MAPK, as well as novel links to neuroinflammation, NFAT and PKCθ signalling. EA presented similar transcriptomic profiles to PGA and HC. Despite the higher proportion of bacterial colonization in NA, no changes were observed in the transcriptomic profiles of severe asthma culture positive compared with severe asthma culture negative. NA features a distinct transcriptomic profile with seven pathways enriched in NA compared to EA, PGA and HC. All those with severe asthma had significant enrichment for SUMOylation, basal cell carcinoma signalling and Wnt/β-catenin pathways compared to HC, despite high-dose inhaled corticosteroids. These findings contribute to the understanding of mechanistic pathways in endobronchial biopsies associated with NA and identify potential novel treatment targets for severe asthma.