Abstract
Neutrophil trafficking, homeostatic and pathogen elicited, depends upon chemoattractant receptors triggering heterotrimeric G-protein Gαiβγ signaling, whose magnitude and kinetics are governed by RGS protein/Gαi interactions. RGS proteins typically limit Gαi signaling by reducing the duration that Gαi 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-Gαi2 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 Gαi2/RGS protein interactions both limit and facilitate Gαi2 signaling thereby promoting normal neutrophil trafficking, aging, and clearance.
Highlights
Signaling via the chemokine receptors CXCR2 and CXCR4 plays several essential roles in neutrophil trafficking
Our studies indicate the G184S Gai2 mutation causes an initial misbalance in the bone marrow (BM) between the CXCR4 mediated retention signal and the CXCR2 mediated mobilization signal
We determined the numbers of neutrophils in the blood, BM, and spleen of mice reconstituted with WT or G184S BM
Summary
Signaling via the chemokine receptors CXCR2 and CXCR4 plays several essential roles in neutrophil trafficking. CXCR2 and CXCR4 counter regulate the release of mature neutrophils from the bone marrow (BM) into the circulation [1]. Either excessive CXCR4 signaling or a lack of CXCR2 signaling causes myelokathexis [1, 2]. Myelokathexis is the inappropriate retention (kathexis) of neutrophils (myelo) in the BM. CXCR2 signaling triggers diurnal changes in the transcriptional and migratory properties of circulating neutrophils, a process termed neutrophil aging [3, 4]. Bmal1 [brain and muscle aryl hydrocarbon receptor nuclear translocator (ARNT)-like 1, encoded by Arntl] regulated expression of CXCL2 triggers these CXCR2-dependent changes in circulating neutrophils, which are opposed by CXCR4 signaling. Neutrophils released from the BM express high levels of
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