Enrichment of the Janus kinase (JAK) activation signature in severe asthma sputum: Correlation with IL-13 expression

Rationale: Activation of multiple cytokine receptors is reported to play an important role in asthma via the Janus kinases (JAK) pathway. IL-13 is known to activate JAKs. We investigated whether this pathway was activated in the sputum and blood of patients from the U-BIOPRED cohort. Methods: Sputum transcriptomics data from 120 subjects with severe asthma (SA) who were smokers (SAsm) or non-smokers (SAn), mild moderate asthmatics (MMA) or healthy controls (HC). Blood transcriptomic data from 312 subjects was also obtained. We used gene set variation analysis (GSVA) to study the KEGG JAK-STAT signalling pathway. IL-13 expression in sputum was detected by SomaScan. Results: The JAK-STAT signalling pathway was enriched in the sputum of asthmatic subjects compared to HC although this was only significant in the SAn group (p=0.01). Subgrouping asthmatics according to their sputum granulocyte status indicated that patients with neutrophilic and mixed granulocytic asthma had the highest JAK-STAT enrichment compared to HC, eosinophilic asthma and paucigranulocytic asthma (all FDR<10^-6). There was no correlation between JAK-STAT enrichment and sputum IL-13 levels. JAK-STAT activation was seen in blood. Conclusions: High activation of JAK-STAT signalling in neutrophilic and mixed granulocytic asthma suggests that these subjects may be suitable for inhaled anti-JAK therapy.