title: Gαi2 is the essential Gαi protein in immune complex-induced lung disease.
abstract: Heterotrimeric G proteins of the Gα(i) family have been implicated in signaling pathways regulating cell migration in immune diseases. The Gα(i)-protein-coupled C5a receptor is a critical regulator of IgG FcR function in experimental models of immune complex (IC)-induced inflammation. By using mice deficient for Gα(i2) or Gα(i3), we show that Gα(i2) is necessary for neutrophil influx in skin and lung Arthus reactions and agonist-induced neutrophilia in the peritoneum, whereas Gα(i3) plays a less critical but variable role. Detailed analyses of the pulmonary IC-induced inflammatory response revealed several shared functions of Gα(i2) and Gα(i3), including mediating C5a anaphylatoxin receptor-induced activation of macrophages, involvement in alveolar production of chemokines, transition of neutrophils from bone marrow into blood, and modulation of CD11b and CD62L expression that account for neutrophil adhesion to endothelial cells. Interestingly, C5a-stimulated endothelial polymorphonuclear neutrophil transmigration, but not chemotaxis, is enhanced versus reduced in the absence of neutrophil Gα(i3) or Gα(i2), respectively, and knockdown of endothelial Gα(i2) caused decreased transmigration of wild-type neutrophils. These data demonstrate that Gα(i2) and Gα(i3) contribute to inflammation by redundant, overlapping, and Gα(i)-isoform-specific mechanisms, with Gα(i2) exhibiting unique functions in both neutrophils and endothelial cells that appear essential for polymorphonuclear neutrophil recruitment in IC disease.
authors.affiliation: Molecular Immunology Research Unit, Clinical Department of Immunology and Rheumatology, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Kristina
authors.initials: K
authors.lastname: Wiege
authors.forename: Syed R
authors.initials: SR
authors.lastname: Ali
authors.forename: Britta
authors.initials: B
authors.lastname: Gewecke
authors.forename: Ana
authors.initials: A
authors.lastname: Novakovic
authors.forename: Franziska M
authors.initials: FM
authors.lastname: Konrad
authors.forename: Katja
authors.initials: K
authors.lastname: Pexa
authors.forename: Sandra
authors.initials: S
authors.lastname: Beer-Hammer
authors.forename: Jörg
authors.initials: J
authors.lastname: Reutershan
authors.forename: Roland P
authors.initials: RP
authors.lastname: Piekorz
authors.forename: Reinhold E
authors.initials: RE
authors.lastname: Schmidt
authors.forename: Bernd
authors.initials: B
authors.lastname: Nürnberg
authors.forename: J Engelbert
authors.initials: JE
authors.lastname: Gessner
mesh_terms: D055371:Acute Lung Injury / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D000818:Animals; D001183:Arthus Reaction / Q000235:genetics / Q000276:immunology / Q000473:pathology; D002448:Cell Adhesion / Q000235:genetics / Q000276:immunology; D002634:Chemotaxis, Leukocyte / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D004730:Endothelium, Vascular / Q000166:cytology / Q000276:immunology / Q000473:pathology; D051960:GTP-Binding Protein alpha Subunit, Gi2 / Q000172:deficiency / Q000502:physiology*; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000502:physiology; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000166:cytology / Q000276:immunology / Q000473:pathology; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
chemical_list: D051960:GTP-Binding Protein alpha Subunit, Gi2; D019206:GTP-Binding Protein alpha Subunits, Gi-Go