title: Gαi2 and Gαi3 Differentially Regulate Arrest from Flow and Chemotaxis in Mouse Neutrophils.
abstract: 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 Gαi2- and Gαi3-containing heterotrimeric G proteins. Neutrophils arrest in response to CXCR2 stimulation. This is defective in Gαi2-deficient neutrophils. In this study, we show that Gαi3-deficient neutrophils showed reduced transmigration but normal arrest in mice. We also tested Gαi2- or Gαi3-deficient neutrophils in a CXCL1 gradient generated by a microfluidic device. Gαi3-, but not Gαi2-, deficient neutrophils showed significantly reduced migration and directionality. This was confirmed in a model of sterile inflammation in vivo. Gαi2-, but not Gαi3-, deficient neutrophils showed decreased Ca(2+) flux in response to CXCR2 stimulation. Conversely, Gαi3-, but not Gαi2-, deficient neutrophils exhibited reduced AKT phosphorylation upon CXCR2 stimulation. We conclude that Gαi2 controls arrest and Gαi3 controls transmigration and chemotaxis in response to chemokine stimulation of neutrophils.
authors.affiliation: Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037;
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kuwano
authors.affiliation: Department of Physics, University of California, San Diego, La Jolla, CA 92093; and.
authors.forename: Micha
authors.initials: M
authors.lastname: Adler
authors.affiliation: Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037;
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Physics, University of California, San Diego, La Jolla, CA 92093; and.
authors.forename: Alex
authors.initials: A
authors.lastname: Groisman
authors.affiliation: Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037; Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093 Klaus@lji.org.
authors.forename: Klaus
authors.initials: K
authors.lastname: Ley
mesh_terms: D000818:Animals; D020013:Calcium Signaling / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D002478:Cells, Cultured; D054360:Chemokine CXCL1 / Q000378:metabolism; D002633:Chemotaxis / Q000235:genetics; D051960:GTP-Binding Protein alpha Subunit, Gi2 / Q000235:genetics / Q000378:metabolism*; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology*; D011485:Protein Binding; D023063:Receptors, Interleukin-8B / Q000378:metabolism; D057705:Transendothelial and Transepithelial Migration / Q000235:genetics
chemical_list: D054360:Chemokine CXCL1; D023063:Receptors, Interleukin-8B; D051960:GTP-Binding Protein alpha Subunit, Gi2; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; C417708:Gnai3 protein, mouse