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Neutrophil trafficking, homeostatic and pathogen elicited, depends upon chemoattractant receptors triggering heterotrimeric G-protein Gα i β γ  signaling, whose magnitude and kinetics are governed by RGS protein/Gα i  interactions. RGS proteins typically limit Gα i  signaling by reducing the duration that Gα i  subunits remain GTP bound and able to activate downstream effectors. Yet how in totality RGS proteins shape neutrophil chemoattractant receptor activated responses remains unclear. Here, we show that C57Bl/6 mouse neutrophils containing a genomic knock-in of a mutation that disables all RGS protein-Gα i2  interactions (G184S) cannot properly balance chemoattractant receptor signaling, nor appropriately respond to inflammatory insults. Mutant neutrophils accumulate in mouse bone marrow, spleen, lung, and liver; despite neutropenia and an intrinsic inability to properly mobilize from the bone marrow.  In vitro  they rapidly adhere to ICAM-1 coated plates, but  in vivo  they poorly adhere to blood vessel endothelium. Those few neutrophils that cross blood vessels and enter tissues migrate haphazardly. Following Concanavalin-A administration fragmented G184S neutrophils accumulate in liver sinusoids leading to thrombo-inflammation and perivasculitis. Thus, neutrophil Gα i2 /RGS protein interactions both limit and facilitate Gα i2  signaling thereby promoting normal neutrophil trafficking, aging, and clearance.

Unrestrained Gαi2 Signaling Disrupts Neutrophil Trafficking, Aging, and Clearance