title: Complement component C1q regulates macrophage expression of Mer tyrosine kinase to promote clearance of apoptotic cells.
abstract: Failure to efficiently clear apoptotic cells is linked to defects in development and the onset of autoimmunity. Complement component C1q is required for efficient engulfment of apoptotic cells in mice and humans; however, the molecular mechanisms leading to C1q-dependent engulfment are not fully understood. In this study, we used primary mouse macrophages to identify and characterize a novel molecular mechanism for macrophage-mediated C1q-dependent engulfment of apoptotic cells. We found that macrophage activation with C1q resulted in cycloheximide-sensitive enhanced engulfment, indicating a requirement for de novo protein synthesis. To investigate the cycloheximide-sensitive pathway, C1q-elicited macrophage transcripts were identified by microarray. C1q triggered the expression of Mer tyrosine kinase (Mer) and the Mer ligand growth arrest-specific 6: a receptor-ligand pair that mediates clearance of apoptotic cells. Full-length native C1q, and not the collagen-like tail or heat-denatured protein, stimulated Mer expression. This novel pathway is specific to C1q because mannose-binding lectin, a related collectin, failed to upregulate Mer expression and function. Soluble Mer-Fc fusion protein inhibited C1q-dependent engulfment of apoptotic cells, indicating a requirement for Mer. Moreover, Mer-deficient macrophages failed to respond to C1q with enhanced engulfment. Our results suggest that C1q elicits a macrophage phenotype specifically tailored for apoptotic cell clearance, and these data are consistent with the established requirement for C1q in prevention of autoimmunity.
authors.affiliation: Department of Biological Sciences, Eck Institute for Global Health, University of Notre Dame, Notre Dame, IN 46556, USA.
authors.forename: Manuel D
authors.initials: MD
authors.lastname: Galvan
authors.forename: Deborah B
authors.initials: DB
authors.lastname: Foreman
authors.forename: Erliang
authors.initials: E
authors.lastname: Zeng
authors.forename: John C
authors.initials: JC
authors.lastname: Tan
authors.forename: Suzanne S
authors.initials: SS
authors.lastname: Bohlson
mesh_terms: D000818:Animals; D017209:Apoptosis; D015551:Autoimmunity; D003167:Complement Activation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D015922:Complement C1q / Q000235:genetics / Q000276:immunology*; D003513:Cycloheximide / Q000494:pharmacology; D017353:Gene Deletion; D005786:Gene Expression Regulation; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D061251:Primary Cell Culture; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000276:immunology*; D020794:Receptor Protein-Tyrosine Kinases / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000494:pharmacology; D015398:Signal Transduction; D000076202:c-Mer Tyrosine Kinase
chemical_list: D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D015922:Complement C1q; D003513:Cycloheximide; C490767:Mertk protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D000076202:c-Mer Tyrosine Kinase