TY - JOUR
T1 - Gαi2 and Gαi3 differentially regulate arrest from flow and chemotaxis in mouse neutrophils
AU - Kuwano, Yoshihiro
AU - Adler, Micha
AU - Zhang, Hong
AU - Groisman, Alex
AU - Ley, Klaus
N1 - Funding Information:
This work was supported by National Institutes of Health Grant HL 111969 (to K.L.). Y.K. was supported by a postdoctoral fellowship grant from the Japan Society for the Promotion of Science.
PY - 2016/5/1
Y1 - 2016/5/1
N2 - Leukocyte recruitment to inflammation sites progresses in a multistep cascade. Chemokines regulate multiple steps of the cascade, including arrest, transmigration, and chemotaxis. The most important chemokine receptor in mouse neutrophils is CXCR2, which couples through Gai2-and Gai3-containing heterotrimeric G proteins. Neutrophils arrest in response to CXCR2 stimulation. This is defective in Gai2-deficient neutrophils. In this study, we show that Gai3-deficient neutrophils showed reduced transmigration but normal arrest in mice. We also tested Gai2-or Gai3-deficient neutrophils in a CXCL1 gradient generated by a microfluidic device. Gai3-, but not Gai2-, deficient neutrophils showed significantly reduced migration and directionality. This was confirmed in a model of sterile inflammation in vivo. Gai2-, but not Gai3-, deficient neutrophils showed decreased Ca2+ flux in response to CXCR2 stimulation. Conversely, Gai3-, but not Gai2-, deficient neutrophils exhibited reduced AKT phosphorylation upon CXCR2 stimulation. We conclude that Gai2 controls arrest and Gai3 controls transmigration and chemotaxis in response to chemokine stimulation of neutrophils.
AB - Leukocyte recruitment to inflammation sites progresses in a multistep cascade. Chemokines regulate multiple steps of the cascade, including arrest, transmigration, and chemotaxis. The most important chemokine receptor in mouse neutrophils is CXCR2, which couples through Gai2-and Gai3-containing heterotrimeric G proteins. Neutrophils arrest in response to CXCR2 stimulation. This is defective in Gai2-deficient neutrophils. In this study, we show that Gai3-deficient neutrophils showed reduced transmigration but normal arrest in mice. We also tested Gai2-or Gai3-deficient neutrophils in a CXCL1 gradient generated by a microfluidic device. Gai3-, but not Gai2-, deficient neutrophils showed significantly reduced migration and directionality. This was confirmed in a model of sterile inflammation in vivo. Gai2-, but not Gai3-, deficient neutrophils showed decreased Ca2+ flux in response to CXCR2 stimulation. Conversely, Gai3-, but not Gai2-, deficient neutrophils exhibited reduced AKT phosphorylation upon CXCR2 stimulation. We conclude that Gai2 controls arrest and Gai3 controls transmigration and chemotaxis in response to chemokine stimulation of neutrophils.
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U2 - 10.4049/jimmunol.1500532
DO - 10.4049/jimmunol.1500532
M3 - Article
C2 - 26976957
AN - SCOPUS:84974779216
SN - 0022-1767
VL - 196
SP - 3828
EP - 3833
JO - Journal of Immunology
JF - Journal of Immunology
IS - 9
ER -