Regulator of G protein signaling 5 restricts neutrophil chemotaxis and trafficking

Abstract

Neutrophils are white blood cells that are mobilized to damaged tissues and to sites of pathogen invasion, providing the first line of host defense. Chemokines displayed on the surface of blood vessels promote migration of neutrophils to these sites, and tissue- and pathogen-derived chemoattractant signals, including -formylmethionylleucylphenylalanine (fMLP), elicit further migration to sites of infection. Although nearly all chemoattractant receptors use heterotrimeric G proteins to transmit signals, many of the mechanisms lying downstream of chemoattractant receptors that either promote or limit neutrophil motility are incompletely defined. Here, we show that regulator of G protein signaling 5 (RGS5), a protein that modulates G protein activity, is expressed in both human and murine neutrophils. We detected significantly more neutrophils in the airways of mice than WT counterparts following acute respiratory virus infection and in the peritoneum in response to injection of thioglycollate, a biochemical proinflammatory stimulus. RGS5-deficient neutrophils responded with increased chemotaxis elicited by the chemokines CC motif chemokine ligand 1 (CXCL1), CXCL2, and CXCL12 but not fMLP. Moreover, adhesion of these cells was increased in the presence of both CXCL2 and fMLP. In summary, our results indicate that RGS5 deficiency increases chemotaxis and adhesion, leading to more efficient neutrophil mobilization to inflamed tissues in mice. These findings suggest that RGS5 expression and activity in neutrophils determine their migrational patterns in the complex microenvironments characteristic of inflamed tissues.

Mechanisms of Maintenance of Foot-and-Mouth Disease Virus Persistence Inferred From Genes Differentially Expressed in Nasopharyngeal Epithelia of Virus Carriers and Non-carriers

“…Cathepsins are components of neutrophil granules, and the expression of three cathepsins (CTSC, CTSF, and CTSV) was significantly lower in carriers than in noncarriers. CD38 is important for neutrophil migration (38,39), whereas RGS5 inhibits neutrophil chemotaxis and trafficking (41). CD38 expression was lower and RGS5 was higher in carriers than in non-carriers.…”

Unrestrained Gαi2Signaling Disrupts Normal Neutrophil Trafficking, Aging, and Clearance

“…This can adversely affect the kinetics of the signal transduction pathways (Hwang et al, 2017). Cells including neutrophils that lack an individual RGS protein typically exhibit enhanced GPCR signaling (Balenga et al, 2014;Chan et al, 2018;Kehrl, 2016;Xie et al, 2016). Furthermore, studies of the G184S mice have largely reported augmented GPCR-linked Gαi signaling (Neubig, 2015), yet past studies examining leukocyte chemoattractant receptors have largely reported diminished signaling (Cho et al, 2012;Hwang et al, 2015;Hwang et al, 2017).…”

“…Loss of Rgs2 in mice increases neutrophil recruitment to inflamed lungs (George et al, 2017;George et al, 2018). Despite its low expression level, loss of Rgs5 in mice also leads to a more robust recruitment of neutrophils to inflamed lungs (Chan et al, 2018). In addition, purified neutrophils from these mice had exaggerated responses to CXCR2 and CXCR4 ligands (Chan et al, 2018).…”

“…Despite its low expression level, loss of Rgs5 in mice also leads to a more robust recruitment of neutrophils to inflamed lungs (Chan et al, 2018). In addition, purified neutrophils from these mice had exaggerated responses to CXCR2 and CXCR4 ligands (Chan et al, 2018). Since the loss an of individual RGS proteins often causes a relatively mild phenotype, perhaps a consequence of their redundant expression profiles, we have made use of a genetically modified mouse that has a mutation, which replaces glycine 184 in the Gαi2 protein with a serine (Huang et al, 2006;Lan et al, 1998).…”

Unrestrained Gαi2 Signaling Disrupts Neutrophil Trafficking, Aging, and Clearance

“…Loss of Rgs2 in mice increases neutrophil recruitment to inflamed lungs ( 12 , 13 ). Despite its low expression level, loss of Rgs5 in mice also leads to a more robust recruitment of neutrophils to inflamed lungs ( 14 ). In addition, purified neutrophils from these mice had exaggerated responses to CXCR2 and CXCR4 ligands ( 14 ).…”