Central role for phosphoinositide-3-kinase gamma/delta dependent signalling in eosinophilic pulmonary inflammation driven by innate lymphoid cells

Le résumé fourni par la source

Severe eosinophilic asthma remains a clinical burden, potentially due to the multiple mechanisms by which type 2 inflammation can arise. Here we show how epithelial alarmin stimulation of innate lymphoid type 2 cells (ILC2s) can promote Th2 cell activity and subsequent eosinophil influx to the lung via mechanisms dependent upon PI3Kγ and δ isoform activity. A PI3Kgamma and delta (PI3Kγδ) mRNA signature identified a Ubiopred severe asthmatic patient segment with high sputum eosinophil content and a Th2/ILC2/alarmin endotype. Evaluation of potent PI3K inhibitors with γ, δ or dual isoform selectivity supported a role in this endotype as follows: PI3Kγ mediated eosinophil degranulation in an in vitro asthmatic subject blood assay. PI3Kδ-dependent IL-33 signalling/ILC2 activity was observed in an in vitro blood assay. In vivo activity of an inhaled PI3Kγδ inhibitor was demonstrated within a murine mechanistic model of IL-33/ILC2-dependent eosinophil influx, and further confirmed using PI3Kγ knockout and PI3Kδ kinase dead knock-in mice. Finally, we demonstrated therapeutic efficacy of PI3Kγδ pathway inhibition on Th2 mediator release and subsequent eosinophil influx in a rodent in vivo model of pulmonary inflammation. These data indicate a central role for both PI3Kγ and δ isoforms in eosinophilic pulmonary inflammation driven by epithelial damage and innate lymphoid cells, and thereby highlight the therapeutic potential of an inhaled dual PI3Kγδ dual inhibitor in severe eosinophilic asthma.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.