Thesis defense Hugo Bergereau

Equipe

Team III - Vascular & Pulmonary Diseases

Directeur de thèse

Vincent Sauzeau

Présidente du jury 

Patricia Lemarchand, MD, PhD, PU, Pneumologue, Nantes Université

Rapporteurs

Mustapha Si-Tahar, PhD, DR, Inserm U1100, Faculté de médecine de Tours
Thomas Trian, MD, PhD, PU, Université de Bordeaux

Examinateurs

Christophe Desmet, PhD, Associate Professor, Université de Liège
Laure Dumoutier, PhD, Professeure, Maître de Recherche, Université catholique de Louvain

Abstract

Background: Asthma a chronic pulmonary disease characterized by exacerbated inflammation, airway hyper-responsiveness and remodeling. Recently, we have demonstrated that a pharmacological inhibition of Rac1 decreased eosinophil infiltration in an experimental model, suggesting that Rac1 could be a relevant target to treat severe asthma inflammation. In this study, we aim to identify the role of Rac1 in eosinophil and investigate its involvement in severe asthma.

Methods: To define the role of Rac1 in eosinophil function, degranulation signaling pathway was analyzed in vitro using bone marrow derived eosinophils from naive and eosinophil specific Knock-Out of Rac1. In addition, these models were exposed to allergens (house dust mite extract) to decipher the impact of Rac1 deletion on physiopathology of severe asthma.

Results :Rac1 is active in eosinophil in asthmatic experimental model and in asthmatic patients’ biopsies. The specific deletion of Rac1 in eosinophil improved smooth muscle thickening and bronchoconstrictor response to methacholine, without affecting inflammatory infiltration.  We further demonstrated that Rac1 activation in eosinophil is involved in the EPX release during degranulation induced by PAF, RANTES and TNF-a. Moreover, Rac1 activation is involved in the migration of secretion vesicles to plasma membrane, though the PLC ß2/IP3R calcium pathway during eosinophil degranulation. Thereafter, we have demonstrated that Rac1 is also involved in the degranulation of eosinophils derived from blood of healthy and severe asthmatic patients.

Conclusion: Our data highlight an essential role of Rac1 in the degranulation of eosinophil though calcium signaling pathway during severe asthma, leading to the development of airway remodeling and hyper-responsiveness. This study contributes to reveal Rac1 as an attractive target in severe asthma.
Keywords: Rac1, eosinophil, asthma, inflammation, airway hyper-responsiveness, PLC ß2, migration