Glucocorticoids Relieve Collectin-Driven Suppression of Apoptotic Cell Uptake in Murine Alveolar Macrophages through Downregulation of SIRPα

The lung environment actively inhibits apoptotic cell (AC) uptake by alveolar macrophages (AMos) via lung collectin signaling through signal regulatory protein a (SIRP alpha). Even brief glucocorticoid (GC) treatment during maturation of human blood monocyte-derived or murine bone marrow-derived macrophages (Mos) increases their AC uptake. Whether GCs similarly impact differentiated tissue Mos and the mechanisms for this rapid response are unknown and important to define, given the widespread therapeutic use of inhaled GCs. We found that the GC fluticasone rapidly and dose-dependently increased AC uptake by murine AMos without a requirement for protein synthesis. Fluticasone rapidly suppressed AMo expression of SIRP alpha mRNA and surface protein, and also activated a more delayed, translation-dependent upregulation of AC recognition receptors that was not required for the early increase in AC uptake. Consistent with a role for SIRP alpha suppression in rapid GC action, murine peritoneal Mos that had not been exposed to lung collectins showed delayed, but not rapid, increase in AC uptake. However, pretreatment of peritoneal Mos with the lung collectin surfactant protein D inhibited AC uptake, and fluticasone treatment rapidly reversed this inhibition. Thus, GCs act not only by upregulating AC recognition receptors during Mo maturation but also via a novel rapid downregulation of SIRP alpha expression by differentiated tissue Mos. Release of AMos from inhibition of AC uptake by lung collectins may, in part, explain the beneficial role of inhaled GCs in inflammatory lung diseases, especially emphysema, in which there is both increased lung parenchymal cell apoptosis and defective AC uptake by AMos. The Journal of Immunology, 2012, 189: 112-119.