title: C1q Modulates the Response to TLR7 Stimulation by Pristane-Primed Macrophages: Implications for Pristane-Induced Lupus.
abstract: The complement component C1q is known to play a controversial role in the pathogenesis of systemic lupus erythematosus, but the underlying mechanisms remain poorly understood. Intraperitoneal injection of pristane induces a lupus-like syndrome whose pathogenesis implicates the secretion of type I IFN by CD11b(+) Ly6C(high) inflammatory monocytes in a TLR7-dependent fashion. C1q was also shown to influence the secretion of IFN-α. In this study, we explored whether C1q deficiency could affect pristane-induced lupus. Surprisingly, C1qa(-/-) mice developed lower titers of circulating Abs and milder arthritis compared with the controls. In keeping with the clinical scores, 2 wk after pristane injection the peritoneal recruitment of CD11b(+) Ly6C(high) inflammatory monocytes in C1qa(-/-) mice was impaired. Furthermore, C1q-deficient pristane-primed resident peritoneal macrophages secreted significantly less CCL3, CCL2, CXCL1, and IL-6 when stimulated in vitro with TLR7 ligand. Replenishing C1q in vivo during the pristane-priming phase rectified this defect. Conversely, pristane-primed macrophages from C3-deficient mice did not show impaired cytokine production. These findings demonstrate that C1q deficiency impairs the TLR7-dependent chemokine production by pristane-primed peritoneal macrophages and suggest that C1q, and not C3, is involved in the handling of pristane by phagocytic cells, which is required to trigger disease in this model.
authors.affiliation: Centre for Complement and Inflammation Research, Division of Immunology and Inflammation, Department of Medicine, Imperial College London, London W12 0NN, United Kingdom; Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Science, Botnar Research Centre, University of Oxford, Oxford OX3 7LD, United Kingdom; and francesco.carlucci@kennedy.ox.ac.uk.
authors.forename: Francesco
authors.initials: F
authors.lastname: Carlucci
authors.affiliation: Centre for Complement and Inflammation Research, Division of Immunology and Inflammation, Department of Medicine, Imperial College London, London W12 0NN, United Kingdom;
authors.forename: Attia
authors.initials: A
authors.lastname: Ishaque
authors.affiliation: Centre for Complement and Inflammation Research, Division of Immunology and Inflammation, Department of Medicine, Imperial College London, London W12 0NN, United Kingdom;
authors.forename: Guang Sheng
authors.initials: GS
authors.lastname: Ling
authors.affiliation: Centre for Complement and Inflammation Research, Division of Immunology and Inflammation, Department of Medicine, Imperial College London, London W12 0NN, United Kingdom;
authors.forename: Marta
authors.initials: M
authors.lastname: Szajna
authors.affiliation: Department of Histopathology, Imperial College Healthcare National Health Service Trust, Charing Cross Hospital, London W6 8RP, United Kingdom.
authors.forename: Ann
authors.initials: A
authors.lastname: Sandison
authors.affiliation: Department of Histopathology, Imperial College Healthcare National Health Service Trust, Charing Cross Hospital, London W6 8RP, United Kingdom.
authors.forename: Philippe
authors.initials: P
authors.lastname: Donatien
authors.affiliation: Centre for Complement and Inflammation Research, Division of Immunology and Inflammation, Department of Medicine, Imperial College London, London W12 0NN, United Kingdom;
authors.forename: H Terence
authors.identifier: http://orcid.org/0000-0002-8950-1041
authors.initials: HT
authors.lastname: Cook
authors.affiliation: Centre for Complement and Inflammation Research, Division of Immunology and Inflammation, Department of Medicine, Imperial College London, London W12 0NN, United Kingdom;
authors.forename: Marina
authors.initials: M
authors.lastname: Botto
mesh_terms: D000818:Animals; D001168:Arthritis / Q000276:immunology; D001323:Autoantibodies / Q000096:biosynthesis; D018925:Chemokines / Q000096:biosynthesis; D015922:Complement C1q / Q000172:deficiency* / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D007369:Interferon Inducers / Q000494:pharmacology; D016898:Interferon-alpha / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000503:physiopathology; D008262:Macrophage Activation; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology*; D008807:Mice, Inbred BALB C; D009000:Monocytes / Q000276:immunology; D011070:Poly I-C / Q000494:pharmacology; D013729:Terpenes / Q000008:administration & dosage*; D051199:Toll-Like Receptor 7 / Q000276:immunology*
chemical_list: D001323:Autoantibodies; D018925:Chemokines; D016207:Cytokines; D007369:Interferon Inducers; D016898:Interferon-alpha; D013729:Terpenes; D051199:Toll-Like Receptor 7; C009042:pristane; D015922:Complement C1q; D011070:Poly I-C