1. Gαi2 is the essential Gαi protein in immune complex-induced lung disease.
- Author
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Wiege K, Ali SR, Gewecke B, Novakovic A, Konrad FM, Pexa K, Beer-Hammer S, Reutershan J, Piekorz RP, Schmidt RE, Nürnberg B, and Gessner JE
- Subjects
- Acute Lung Injury genetics, Acute Lung Injury pathology, Animals, Arthus Reaction genetics, Arthus Reaction immunology, Arthus Reaction pathology, Cell Adhesion genetics, Cell Adhesion immunology, Chemotaxis, Leukocyte genetics, Chemotaxis, Leukocyte immunology, Disease Models, Animal, Down-Regulation genetics, Down-Regulation immunology, Endothelium, Vascular cytology, Endothelium, Vascular immunology, Endothelium, Vascular pathology, GTP-Binding Protein alpha Subunit, Gi2 deficiency, GTP-Binding Protein alpha Subunits, Gi-Go physiology, Mice, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Knockout, Neutrophils cytology, Neutrophils immunology, Neutrophils pathology, Up-Regulation genetics, Up-Regulation immunology, Acute Lung Injury immunology, GTP-Binding Protein alpha Subunit, Gi2 physiology
- 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.
- Published
- 2013
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