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

Abstract Background Poor clearance of apoptotic cells has been suggested to contribute to severe asthma, but whether uptake of apoptotic cells by lung phagocytes might dampen House Dust Mite (HDM)-induced lung inflammation has not been shown. Objective We investigated if apoptotic cell engulfment in the murine lung impacts the development of allergen-induced asthmatic airway inflammation and which immune modulating mechanisms were activated. Methods Apoptotic cells were infused into the lungs of mice challenged with HDM allergen and lung inflammation, expression of suppressive molecules, and induction of Treg were monitored. Additionally, an adenosine receptor agonist was tested to study the mechanism of suppression elicited by apoptotic cells. Results Apoptotic cell uptake by lung alveolar macrophages suppressed HDM-driven allergic asthma. This was associated with promoting the Treg-inducing molecule retinoic acid, inhibiting inflammatory cytokine production, and making macrophages more susceptible to receiving suppressive signals from adenosine. Correspondingly, adenosine receptor agonist treatment also limited HDM-driven allergic airway inflammation through an action on alveolar macrophages. Conclusion These data provide insight into the mechanisms by which lung macrophages dampen allergen-induced airway inflammation. They suggest that targeting lung macrophages to increase their phagocytic capacity, enhance their ability to make retinoic acid, dampen their capacity to make inflammatory cytokines, and increase their responsiveness to adenosine, could be useful to suppress allergic responses.