Introduction: Molecular mechanisms underlying inflammation processes during severe asthma remains poorly understood. We previously demonstrated in a murine severe asthma model that inhibiting the small GTPase Rac lowered the infiltration of immune cells within the bronchi (Dilasser, F. et al. Thorax 2021;76:326-334).

Aims and objectives: We aim to identify inflammatory cells displaying a Rac activation during severe asthma and highlight affected pathways.

Methods: We quantified active Rac-GTP by immune fluorescence in bronchial biopsies from severe asthmatic patients (NaRacAS study, NCT03325088) and by flow cytometry within inflammatory cells in a murine severe allergic asthma model (house dust mite). Using bone-marrow derived murine eosinophils, we studied the level of activation of Rac during eosinophils maturation and degranulation induced by platelet activating factor (PAF).

Results: Epithelial cells, smooth muscle cells and inflammatory cells display intense Rac-GTP signal in bronchial biopsies from severe asthmatic patients. Macrophages and eosinophils increase their Rac-GTP signal in asthmatic mice compared with controls. Bone marrow derived eosinophils presented an activation of Rac while differentiating. Eosinophils stimulated by PAF show a Rac-GTP membrane signal compared to unstimulated ones. Eosinophils treated with a Rac inhibitor had impaired degranulation abilities.

Conclusion: Rac plays important roles in the biology of eosinophils in severe asthma. Research is currently underway to identify Rac activators that could lead to the development of new specific treatments in eosinophilic severe asthma.