Clearance of Apoptotic cells by Lung Macrophages Prevents Development of House Dust Mite-induced Asthmatic Lung Inflammation

Abstract

Abstract Allergen inhalation can cause epithelial damage and induce cell death while driving asthmatic lung inflammation. It has been suggested that patients with severe asthma may have a defect in clearance of apoptotic cells, of significance as apoptotic cell phagocytosis is thought important to maintain tissue homeostasis. Previously we have reported that lung resident macrophages in a non-inflamed lung generate regulatory T cells (Tregs) and can promote airway tolerance, and hypothesized that this ability was related to uptake of apoptotic cells. We investigated this by infusing apoptotic thymocytes into the lungs to determine their impact on macrophage function and allergic asthma. We found that lung macrophages were the primary cell to engulf apoptotic cells and this was not modified with intranasal exposure to House Dust Mite (HDM) allergen challenge. The uptake of apoptotic cells by alveolar macrophages in vivo or in vitro resulted in increased expression of RALDH1 and RALDH2, enzymes that drive retinoic acid production. When apoptotic cells were transferred into the lung during sensitization with HDM, eosinophilic airway inflammation, and Th2 cytokine production in the BALF and lung, were significantly reduced compared to mice given viable cells. This was accompanied by an increase in the frequency of antigen-specific Treg in the lung draining lymph nodes. These results indicate that apoptotic cell clearance by lung macrophages is important to maintain airway tolerance and prevent induction of allergic asthma.