title: Macrophages induce the inflammatory response in the pulmonary Arthus reaction through G alpha i2 activation that controls C5aR and Fc receptor cooperation.
abstract: Complement and FcgammaR effector pathways are central triggers of immune inflammation; however, the exact mechanisms for their cooperation with effector cells and their nature remain elusive. In this study we show that in the lung Arthus reaction, the initial contact between immune complexes and alveolar macrophages (AM) results in plasma complement-independent C5a production that causes decreased levels of inhibitory FcgammaRIIB, increased levels of activating FcgammaRIII, and highly induced FcgammaR-mediated TNF-alpha and CXCR2 ligand production. Blockade of C5aR completely reversed such changes. Strikingly, studies of pertussis toxin inhibition show the essential role of G(i)-type G protein signaling in C5aR-mediated control of the regulatory FcgammaR system in vitro, and analysis of the various C5aR-, FcgammaR-, and G(i)-deficient mice verifies the importance of Galpha(i2)-associated C5aR and the FcgammaRIII-FcgammaRIIB receptor pair in lung inflammation in vivo. Moreover, adoptive transfer experiments of C5aR- and FcgammaRIII-positive cells into C5aR- and FcgammaRIII-deficient mice establish AM as responsible effector cells. AM lacking either C5aR or FcgammaRIII do not possess any such inducibility of immune complex disease, whereas reconstitution with FcgammaRIIB-negative AM results in an enhanced pathology. These data suggest that AM function as a cellular link of C5a production and C5aR activation that uses a Galpha(i2)-dependent signal for modulating the two opposing FcgammaR, FcgammaRIIB and FcgammaRIII, in the initiation of the inflammatory cascade in the lung Arthus reaction.
authors.affiliation: Department of Clinical Immunology, Medical School Hannover, Hannover, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Skokowa
authors.forename: Syed R
authors.initials: SR
authors.lastname: Ali
authors.forename: Olga
authors.initials: O
authors.lastname: Felda
authors.forename: Varsha
authors.initials: V
authors.lastname: Kumar
authors.forename: Stephanie
authors.initials: S
authors.lastname: Konrad
authors.forename: Nelli
authors.initials: N
authors.lastname: Shushakova
authors.forename: Reinhold E
authors.initials: RE
authors.lastname: Schmidt
authors.forename: Roland P
authors.initials: RP
authors.lastname: Piekorz
authors.forename: Bernd
authors.initials: B
authors.lastname: Nürnberg
authors.forename: Karsten
authors.initials: K
authors.lastname: Spicher
authors.forename: Lutz
authors.initials: L
authors.lastname: Birnbaumer
authors.forename: Jörg
authors.initials: J
authors.lastname: Zwirner
authors.forename: Jill W C
authors.initials: JW
authors.lastname: Claassens
authors.forename: Josef S
authors.initials: JS
authors.lastname: Verbeek
authors.forename: Nico
authors.initials: N
authors.lastname: van Rooijen
authors.forename: Jörg
authors.initials: J
authors.lastname: Köhl
authors.forename: J Engelbert
authors.initials: JE
authors.lastname: Gessner
mesh_terms: D000818:Animals; D001183:Arthus Reaction / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D002460:Cell Line; D015936:Complement C5a / Q000502:physiology; D051960:GTP-Binding Protein alpha Subunit, Gi2; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism* / Q000502:physiology; D006358:Hot Temperature; D007074:Immunoglobulin G / Q000494:pharmacology; D018836:Inflammation Mediators / Q000378:metabolism* / Q000502:physiology; D008168:Lung / Q000276:immunology / Q000473:pathology*; D008262:Macrophage Activation / Q000276:immunology; D016676:Macrophages, Alveolar / Q000276:immunology* / Q000378:metabolism; D008565:Membrane Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011518:Proto-Oncogene Proteins / Q000378:metabolism* / Q000502:physiology; D020239:Receptor Cross-Talk / Q000276:immunology; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011961:Receptors, Fc / Q000378:metabolism*; D017452:Receptors, IgG / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology
chemical_list: C488033:C5AR1 protein, human; C485700:Fcgr3 protein, mouse; D007074:Immunoglobulin G; D018836:Inflammation Mediators; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement; D011961:Receptors, Fc; D017452:Receptors, IgG; D015936:Complement C5a; D051960:GTP-Binding Protein alpha Subunit, Gi2; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; C498016:Gnai2 protein, mouse