Gαi2 Is the Essential Gαi Protein in Immune Complex–Induced Lung Disease

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.