title: Inflammatory responses induced by lipopolysaccharide are amplified in primary human monocytes but suppressed in macrophages by complement protein C5a.
abstract: Monocytes and macrophages are important innate immune cells equipped with danger-sensing receptors, including complement and Toll-like receptors. Complement protein C5a, acting via C5aR, is shown in this study to differentially modulate LPS-induced inflammatory responses in primary human monocytes versus macrophages. Whereas C5a enhanced secretion of LPS-induced IL-6 and TNF from primary human monocytes, C5a inhibited these responses while increasing IL-10 secretion in donor-matched human monocyte-derived macrophages differentiated by GM-CSF or M-CSF. Gαi/c-Raf/MEK/ERK signaling induced by C5a was amplified in macrophages but not in monocytes by LPS. Accordingly, the Gαi inhibitor pertussis toxin and MEK inhibitor U0126 blocked C5a inhibition of LPS-induced IL-6 and TNF production from macrophages. This synergy was independent of IL-10, PI3K, p38, JNK, and the differentiating agent. Furthermore, C5a did not inhibit IL-6 production from macrophages induced by other TLR agonists that are selective for Toll/IL-1R domain-containing adapter inducing IFN-β (polyinosinic-polycytidylic acid) or MyD88 (imiquimod), demonstrating selectivity for C5a regulation of LPS responses. Finally, suppression of proinflammatory cytokines IL-6 and TNF in macrophages did not compromise antimicrobial activity; instead, C5a enhanced clearance of the Gram-negative bacterial pathogen Salmonella enterica serovar Typhimurium from macrophages. C5aR is thus a regulatory switch that modulates TLR4 signaling via the Gαi/c-Raf/MEK/ERK signaling axis in human macrophages but not monocytes. The differential effects of C5a are consistent with amplifying monocyte proinflammatory responses to systemic danger signals, but attenuating macrophage cytokine responses (without compromising microbicidal activity), thereby restraining inflammatory responses to localized infections.
authors.affiliation: Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Vernon
authors.initials: V
authors.lastname: Seow
authors.forename: Junxian
authors.initials: J
authors.lastname: Lim
authors.forename: Abishek
authors.initials: A
authors.lastname: Iyer
authors.forename: Jacky Y
authors.initials: JY
authors.lastname: Suen
authors.forename: Juliana K
authors.initials: JK
authors.lastname: Ariffin
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Hohenhaus
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Sweet
authors.forename: David P
authors.initials: DP
authors.lastname: Fairlie
mesh_terms: D000634:Aminoquinolines; D002070:Butadienes / Q000494:pharmacology; D002478:Cells, Cultured; D015936:Complement C5a / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000037:antagonists & inhibitors / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D006801:Humans; D000077271:Imiquimod; D007249:Inflammation / Q000139:chemically induced; D016753:Interleukin-10 / Q000096:biosynthesis / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008070:Lipopolysaccharides; D020935:MAP Kinase Signaling System / Q000276:immunology; D016173:Macrophage Colony-Stimulating Factor; D008264:Macrophages / Q000378:metabolism*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009000:Monocytes / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D037342:Pertussis Toxin / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011070:Poly I-C; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement / Q000378:metabolism*; D012486:Salmonella typhimurium / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D048069:Tumor Necrosis Factors / Q000378:metabolism
chemical_list: D000634:Aminoquinolines; D002070:Butadienes; C488033:C5AR1 protein, human; D015850:Interleukin-6; D008070:Lipopolysaccharides; D009570:Nitriles; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D048069:Tumor Necrosis Factors; C113580:U 0126; D016753:Interleukin-10; D015936:Complement C5a; D016173:Macrophage Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D037342:Pertussis Toxin; D019869:Phosphatidylinositol 3-Kinases; D019908:Proto-Oncogene Proteins c-raf; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D011070:Poly I-C; D000077271:Imiquimod