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

The lung environment actively inhibits apoptotic cell (AC) uptake by alveolar macrophages (AMøs) via lung collectin signaling through signal regulatory protein a (SIRPa). Even brief glucocorticoid (GC) treatment during maturation of human blood monocyte-derived or murine bone marrow-derived macrophages (Møs) increases their AC uptake. Whether GCs similarly impact differentiated tissue Møs 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 AMøs without a requirement for protein synthesis. Fluticasone rapidly suppressed AMø expression of SIRPa 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 SIRPa suppression in rapid GC action, murine peritoneal Møs that had not been exposed to lung collectins showed delayed, but not rapid, increase in AC uptake. However, pretreatment of peritoneal Møs 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 Mø maturation but also via a novel rapid downregu-lation of SIRPa expression by differentiated tissue Møs. Release of AMøs 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 AMøs. A poptotic cell (AC) uptake by phagocytes, also termed efferocytosis (1), is an essential process that promotes the resolution of injury and inflammation, facilitating tissue repair in the lung and throughout the body (2). Impaired AC uptake has been found in phagocytes from human subjects with cystic fibrosis, asthma, and chronic obstructive pulmonary disease (COPD) (3–6). Because defective AC clearance clearly contributes to autoimmunity in murine models (7, 8), and because there is growing evidence that human emphysema may have an autoim-mune component (9, 10), potential therapies designed to bolster AC clearance have been proposed (11). This issue is of considerable importance, because COPD is now the third leading cause of death in the United States, and has been projected by the World Health Organization to become the leading worldwide cause of death by mid-21st century (12). In seeming contradiction to the importance of AC clearance, the resident lung phagocyte, …