PI3Kδ inhibition prevents IL33, ILC2s and inflammatory eosinophils in persistent airway inflammation

Sorif Uddin, Augustin Amour, Chris D Edwards, Matthew G Williamson, Simon Hall, Lisa Lione, Edith M Hessel

Research output: Contribution to journalArticlepeer-review

25 Downloads (Pure)

Abstract

Background: Phosphoinositide-3-kinase-delta (PI3Kδ) inhibition is a promising therapeutic approach for inflammatory conditions due to its role in leucocyte proliferation, migration and activation. However, the effect of PI3Kδ inhibition on group 2 innate lymphoid cells (ILC2s) and inflammatory eosinophils remains unknown. Using a murine model exhibiting persistent airway inflammation we sought to understand the effect of PI3Kδ inhibition, montelukast and anti-IL5 antibody treatment on IL33 expression, group-2-innate lymphoid cells, inflammatory eosinophils, and goblet cell metaplasia. Results: Mice were sensitised to house dust mite and after allowing inflammation to resolve, were re-challenged with house dust mite to re-initiate airway inflammation. ILC2s were found to persist in the airways following house dust mite sensitisation and after re-challenge their numbers increased further along with accumulation of inflammatory eosinophils. In contrast to montelukast or anti-IL5 antibody treatment, PI3Kδ inhibition ablated IL33 expression and prevented group-2-innate lymphoid cell accumulation. Only PI3Kδ inhibition and IL5 neutralization reduced the infiltration of inflammatory eosinophils. Moreover, PI3Kδ inhibition reduced goblet cell metaplasia. Conclusions: Hence, we show that PI3Kδ inhibition dampens allergic inflammatory responses by ablating key cell types and cytokines involved in T-helper-2-driven inflammatory responses.

Original languageEnglish
Article number78
Pages (from-to)78
JournalBMC Immunology
Volume22
Issue number1
Early online date17 Dec 2021
DOIs
Publication statusPublished - 17 Dec 2021

Keywords

  • Goblet cell metaplasia
  • IL33
  • ILC2
  • PI3Kδ
  • Siglec-F inflammatory eosinophils

Fingerprint

Dive into the research topics of 'PI3Kδ inhibition prevents IL33, ILC2s and inflammatory eosinophils in persistent airway inflammation'. Together they form a unique fingerprint.

Cite this