Abstract:
:Neutrophils are first responders rapidly mobilized to inflammatory sites by a tightly regulated, nonredundant hierarchy of chemoattractants. These chemoattractants engage neutrophil cell surface receptors triggering heterotrimeric G-protein Gα(i) subunits to exchange GDP for GTP. By limiting the duration that Gα(i) subunits remain GTP bound, RGS proteins modulate chemoattractant receptor signaling. Here, we show that neutrophils with a genomic knock in of a mutation that disables regulator of G-protein signaling (RGS)-Gα(i2) interactions accumulate in the bone marrow and mobilize poorly to inflammatory sites. These defects are attributable to enhanced sensitivity to background signals, prolonged chemoattractant receptor signaling, and inappropriate CXCR2 downregulation. Intravital imaging revealed a failure of the mutant neutrophils to accumulate at and stabilize sites of sterile inflammation. Furthermore, these mice could not control a nonlethal Staphylococcus aureus infection. Neutrophil RGS proteins establish a threshold for Gα(i) activation, helping to coordinate desensitization mechanisms. Their loss renders neutrophils functionally incompetent.
journal_name
Mol Cell Bioljournal_title
Molecular and cellular biologyauthors
Cho H,Kamenyeva O,Yung S,Gao JL,Hwang IY,Park C,Murphy PM,Neubig RR,Kehrl JHdoi
10.1128/MCB.00651-12subject
Has Abstractpub_date
2012-11-01 00:00:00pages
4561-71issue
22eissn
0270-7306issn
1098-5549pii
MCB.00651-12journal_volume
32pub_type
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