title: Role of surfactant proteins A, D, and C1q in the clearance of apoptotic cells in vivo and in vitro: calreticulin and CD91 as a common collectin receptor complex.
abstract: Removal of cells dying by apoptosis is essential to normal development, maintenance of tissue homeostasis, and resolution of inflammation. Surfactant protein A (SP-A) and surfactant protein D (SP-D) are high abundance pulmonary collectins recently implicated in apoptotic cell clearance in vitro. Other collectins, such as mannose-binding lectin and the collectin-like C1q, have been shown to bind to apoptotic cells and drive ingestion through interaction with calreticulin and CD91 on the phagocyte in vitro. However, only C1q has been shown to enhance apoptotic cell uptake in vivo. We sought to determine the relative importance of SP-A, SP-D, and C1q in pulmonary clearance of apoptotic cells using knockout and overexpressing mice, and to determine the role of calreticulin and CD91 in this process. SP-A, SP-D, and C1q all enhanced apoptotic cell ingestion by resident murine and human alveolar macrophages in vitro. However, only SP-D altered apoptotic cell clearance from the naive murine lung, suggesting that SP-D plays a particularly important role in vivo. Similar to C1q and mannose-binding lectin, SP-A and SP-D bound to apoptotic cells in a localized, patchy pattern and drove apoptotic cell ingestion by phagocytes through a mechanism dependent on calreticulin and CD91. These results suggest that the entire collectin family of innate immune proteins (including C1q) works through a common receptor complex to enhance removal of apoptotic cells, and that collectins are integral, organ-specific components of the clearance machinery.
authors.affiliation: Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine and Pathology, University of Colorado Health Sciences Center, nd Denver, CO, USA.
authors.forename: R William
authors.initials: RW
authors.lastname: Vandivier
authors.forename: Carol Anne
authors.initials: CA
authors.lastname: Ogden
authors.forename: Valerie A
authors.initials: VA
authors.lastname: Fadok
authors.forename: Peter R
authors.initials: PR
authors.lastname: Hoffmann
authors.forename: Kevin K
authors.initials: KK
authors.lastname: Brown
authors.forename: Marina
authors.initials: M
authors.lastname: Botto
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Walport
authors.forename: James H
authors.initials: JH
authors.lastname: Fisher
authors.forename: Peter M
authors.initials: PM
authors.lastname: Henson
authors.forename: Kelly E
authors.initials: KE
authors.lastname: Greene
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D037282:Calreticulin / Q000378:metabolism*; D002450:Cell Communication / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D015922:Complement C1q / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D004912:Erythrocytes / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D006801:Humans; D019169:Jurkat Cells; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000378:metabolism*; D008168:Lung / Q000166:cytology / Q000276:immunology; D046911:Macromolecular Substances; D016676:Macrophages, Alveolar / Q000276:immunology / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism; D010587:Phagocytosis / Q000235:genetics / Q000276:immunology; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D037662:Pulmonary Surfactant-Associated Protein A / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D037663:Pulmonary Surfactant-Associated Protein D / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D037282:Calreticulin; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D046911:Macromolecular Substances; D008565:Membrane Proteins; D037662:Pulmonary Surfactant-Associated Protein A; D037663:Pulmonary Surfactant-Associated Protein D; D015922:Complement C1q