Altered CXCR2 signaling in beta-arrestin-2-deficient mouse models.
CXCR2 is a G-protein-coupled receptor (GPCR) that binds the CXC chemokines, CXCL1-3 and CXCL5-8, and induces intracellular signals associated with chemotaxis. Many adaptor proteins are actively involved in the sequestration, internalization, and trafficking of CXCR2 and transduction of agonist-induced intracellular signaling. We have previously shown that adaptor protein beta-arrestin-2 (betaarr2) plays a crucial role in transducing signals mediated through CXCR2. To further investigate the role of betaarr2 on CXCR2-mediated signaling during acute inflammation, zymosan-induced neutrophils were isolated from peritoneal cavities of betaarr2-deficient (betaarr2(-/-)) and their wild-type (betaarr2(+/+)) littermate mice, and neutrophil CXCR2 signaling activities were determined by measurement of Ca(2+) mobilization, receptor internalization, GTPase activity, and superoxide anion production. The results showed that the deletion of betaarr2 resulted in increased Ca(2+) mobilization, superoxide anion production, and GTPase activity in neutrophils, but decreased receptor internalization relative to wild-type mice. Two animal models, the dorsal air pouch model and the excisional wound healing model, were used to further study the in vivo effects of betaarr2 on CXCR2-mediated neutrophil chemotaxis and on cutaneous wound healing. Surprisingly, the recruitment of neutrophils was increased in response to CXCL1 in the air pouch model and in the excisional wound beds of betaarr2(-/-) mice. Wound re-epithelialization was also significantly faster in betaarr2(-/-) mice than in betaarr2(+/+) mice. Taken together, the data indicate that betaarr2 is a negative regulator for CXCR2 in vivo signaling.
Su
Yingjun
Y
Department of Veterans Affairs, Nashville, TN 37212, USA.
Raghuwanshi
Sandeep K
SK
Yu
Yingchun
Y
Nanney
Lillian B
LB
Richardson
Ricardo M
RM
Richmond
Ann
A
D000818:Animals; D019390:Arrestins / Q000172:deficiency* / Q000235:genetics*; D002465:Cell Movement / Q000502:physiology; D004848:Epithelium / Q000502:physiology; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018448:Models, Immunological; D009504:Neutrophils / Q000378:metabolism / Q000502:physiology; D023063:Receptors, Interleukin-8B / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics*; D014945:Wound Healing / Q000502:physiology; D014947:Wounds and Injuries / Q000378:metabolism / Q000473:pathology; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
C000605258:Arrb2 protein, mouse; D019390:Arrestins; D023063:Receptors, Interleukin-8B; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins