title: GEF-H1 is necessary for neutrophil shear stress-induced migration during inflammation.
abstract: Leukocyte crawling and transendothelial migration (TEM) are potentiated by shear stress caused by blood flow. The mechanism that couples shear stress to migration has not been fully elucidated. We found that mice lacking GEF-H1 (GEF-H1-/-), a RhoA-specific guanine nucleotide exchange factor (GEF), displayed limited migration and recruitment of neutrophils into inflamed tissues. GEF-H1-/-leukocytes were deficient in in vivo crawling and TEM in the postcapillary venules. We demonstrated that although GEF-H1 deficiency had little impact on the migratory properties of neutrophils under static conditions, shear stress triggered GEF-H1-dependent spreading and crawling of neutrophils and relocalization of GEF-H1 to flotillin-2-rich uropods. Our results identify GEF-H1 as a component of the shear stress response machinery in neutrophils required for a fully competent immune response to bacterial infection.
authors.affiliation: Princess Margaret Cancer Center, Toronto, Ontario M5G 1L7, Canada Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5S 1L7, Canada Matrix Dynamics Group, University of Toronto, Toronto, Ontario M5S 3E2, Canada.
authors.forename: Noah
authors.identifier: http://orcid.org/0000-0002-7234-094X
authors.initials: N
authors.lastname: Fine
authors.affiliation: Princess Margaret Cancer Center, Toronto, Ontario M5G 1L7, Canada Department of Immunology, University of Toronto, Toronto, Ontario M5S 1L7, Canada.
authors.forename: Ioannis D
authors.identifier: http://orcid.org/0000-0001-5778-8896
authors.initials: ID
authors.lastname: Dimitriou
authors.affiliation: Toronto General Research Institute, University Health Network, Toronto, Ontario M5G 2C4, Canada.
authors.forename: Jacob
authors.initials: J
authors.lastname: Rullo
authors.affiliation: Princess Margaret Cancer Center, Toronto, Ontario M5G 1L7, Canada.
authors.forename: María José
authors.identifier: http://orcid.org/0000-0002-4782-3800
authors.initials: MJ
authors.lastname: Sandí
authors.affiliation: Immunology Research Group, Department of Physiology and Pharmacology, Calvin, Phoebe and Joan Snyder Institute for Infection, Immunity and Inflammation, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
authors.forename: Björn
authors.identifier: http://orcid.org/0000-0002-5871-4132
authors.initials: B
authors.lastname: Petri
authors.affiliation: Department of Anesthesiology, VU Medical Center, 1081 HV Amsterdam, Netherlands.
authors.forename: Jack
authors.identifier: http://orcid.org/0000-0002-0738-9720
authors.initials: J
authors.lastname: Haitsma
authors.affiliation: Toronto General Research Institute, University Health Network, Toronto, Ontario M5G 2C4, Canada.
authors.forename: Hisham
authors.initials: H
authors.lastname: Ibrahim
authors.affiliation: Princess Margaret Cancer Center, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Jose
authors.initials: J
authors.lastname: La Rose
authors.affiliation: Matrix Dynamics Group, University of Toronto, Toronto, Ontario M5S 3E2, Canada.
authors.forename: Michael
authors.identifier: http://orcid.org/0000-0002-6248-5977
authors.initials: M
authors.lastname: Glogauer
authors.affiliation: Immunology Research Group, Department of Physiology and Pharmacology, Calvin, Phoebe and Joan Snyder Institute for Infection, Immunity and Inflammation, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
authors.forename: Paul
authors.initials: P
authors.lastname: Kubes
authors.affiliation: Toronto General Research Institute, University Health Network, Toronto, Ontario M5G 2C4, Canada.
authors.forename: Myron
authors.identifier: http://orcid.org/0000-0002-1696-2867
authors.initials: M
authors.lastname: Cybulsky
authors.affiliation: Princess Margaret Cancer Center, Toronto, Ontario M5G 1L7, Canada Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5S 1L7, Canada Department of Immunology, University of Toronto, Toronto, Ontario M5S 1L7, Canada Department of Medicine, University of Toronto, Toronto, Ontario M5S 1L7, Canada Toronto General Research Institute, University Health Network, Toronto, Ontario M5G 2C4, Canada rottapel@uhnresearch.ca.
authors.forename: Robert
authors.initials: R
authors.lastname: Rottapel
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D018922:HL-60 Cells; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000473:pathology*; D051379:Mice; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D009132:Muscles / Q000187:drug effects; D018994:Myosin Light Chains / Q000378:metabolism; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D020556:Neutrophil Infiltration / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D058105:Polymerization / Q000187:drug effects; D064067:Rho Guanine Nucleotide Exchange Factors / Q000172:deficiency / Q000378:metabolism*; D018805:Sepsis / Q000473:pathology; D013314:Stress, Mechanical
chemical_list: C577402:Arhgef2 protein, mouse; D018994:Myosin Light Chains; D064067:Rho Guanine Nucleotide Exchange Factors; D009240:N-Formylmethionine Leucyl-Phenylalanine