Projects per year
Background: Eosinophils play a central role in the propagation of allergic diseases including asthma. Both recruitment and retention of eosinophils regulate pulmonary eosinophilia but the question of whether alterations in apoptotic cell clearance by phagocytes directly contributes to resolution of allergic airway inflammation remains unexplored.
Objectives: In this study we investigated the role of the receptor tyrosine kinase Mer in mediating apoptotic eosinophil clearance and allergic airway inflammation resolution in vivo in order to establish whether apoptotic cell clearance directly impacts upon the resolution of allergic airway inflammation.
Methods: Alveolar and bone-marrow macrophages were used to study Mer-mediated phagocytosis of apoptotic eosinophils. Allergic airway inflammation resolution was modelled in mice using ovalbumin. To determine apoptotic cell clearance in vivo, fluorescently labeled apoptotic cells were administered intratracheally or eosinophil apoptosis was driven by
administration of dexamethasone.
Results: Inhibition or absence of Mer impaired phagocytosis of apoptotic human and mouse eosinophils by macrophages. Mer-deficient mice displayed delayed resolution of ovalbumin44 induced allergic airway inflammation together with increased airway responsiveness to aerosolized methacholine, elevated bronchoalveolar lavage fluid protein levels, altered cytokine production and an excess of uncleared dying eosinophils after dexamethasone treatment. Alveolar macrophage phagocytosis was significantly Mer-dependent, with the absence of Mer attenuating apoptotic cell clearance in vivo to enhance inflammation in
response to apoptotic cells.
Conclusions: We demonstrate that Mer-mediated apoptotic cell clearance by phagocytes contributes to resolution of allergic airway inflammation, suggesting that augmenting apoptotic cell clearance is a potential therapeutic strategy for treating allergic airway inflammation.
3/07/17 → 4/03/22
The role of cyclin-dependent kinase-9 inhibition in promoting the resolution of chronic inflammation
1/05/13 → 30/10/19
1/04/11 → 31/03/14