title: Glucocorticoids relieve collectin-driven suppression of apoptotic cell uptake in murine alveolar macrophages through downregulation of SIRPα.
abstract: The lung environment actively inhibits apoptotic cell (AC) uptake by alveolar macrophages (AMøs) via lung collectin signaling through signal regulatory protein α (SIRPα). 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 SIRPα 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 SIRPα 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 downregulation of SIRPα 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.
authors.affiliation: Graduate Program in Immunology, University of Michigan Health System, Ann Arbor, MI 48109, USA.
authors.forename: Alexandra L
authors.initials: AL
authors.lastname: McCubbrey
authors.forename: Joanne
authors.initials: J
authors.lastname: Sonstein
authors.forename: Theresa M
authors.initials: TM
authors.lastname: Ames
authors.forename: Christine M
authors.initials: CM
authors.lastname: Freeman
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Curtis
mesh_terms: D000730:Androstadienes / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins / Q000494:pharmacology* / Q000502:physiology; D002478:Cells, Cultured; D037222:Collectins / Q000502:physiology*; D004306:Dose-Response Relationship, Immunologic; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology*; D000068298:Fluticasone; D007108:Immune Tolerance / Q000187:drug effects / Q000276:immunology*; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors* / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
chemical_list: D000730:Androstadienes; D051017:Apoptosis Regulatory Proteins; D037222:Collectins; C501922:Sirpa protein, mouse; D011971:Receptors, Immunologic; D000068298:Fluticasone