Abstract
BackgroundPhosphoinositide-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.ResultsMice 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.ConclusionsHence, we show that PI3Kδ inhibition dampens allergic inflammatory responses by ablating key cell types and cytokines involved in T-helper-2-driven inflammatory responses.
Highlights
Phosphoinositide-3-kinase-delta (PI3Kδ) inhibition is a promising therapeutic approach for inflammatory conditions due to its role in leucocyte proliferation, migration and activation
In order to address this question, we evaluated the effect of PI3Kδ inhibition on IL33 induction, accumulation of Group 2 innate lymphoid cell (ILC2) cells, migration of inflammatory (Siglec-Fhi) eosinophils and initiation of goblet cell metaplasia
3 weeks of repeated topical house dust mite (HDM) sensitisation resulted in persistent pulmonary allergic inflammation and cells involved in the allergic response remained in the lung following a period of resolution The challenge and sensitisation protocol used in the current study (Fig. 1) resulted in establishment of an eosinophilic, neutrophilic and lymphocytic infiltration (p < 0.001, Fig. 2A) into the airways of mice and induced pro-inflammatory cytokines (p < 0.01, Fig. 2B)
Summary
Phosphoinositide-3-kinase-delta (PI3Kδ) inhibition is a promising therapeutic approach for inflammatory conditions due to its role in leucocyte proliferation, migration and activation. 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. Clinical evidence demonstrates that its effectiveness may be more asthma endotype dependent [9, 10] and montelukast may be more appropriate for atopic paediatric and exercise-induced asthma subpopulations [11] Antibodies such as Mepolizumab that target IL5, the cytokine responsible for the activation, proliferation, maturation and survival of eosinophils, have been approved for the treatment of eosinophilic diseases including severe refractory eosinophilic asthma [12]. Phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitors have been developed as potential novel nonsteroidal anti-inflammatory agents for asthma and other pulmonary inflammatory disorders [13,14,15,16]
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