title: The small GTPase Rap1b negatively regulates neutrophil chemotaxis and transcellular diapedesis by inhibiting Akt activation.
abstract: Neutrophils are the first line of cellular defense in response to infections and inflammatory injuries. However, neutrophil activation and accumulation into tissues trigger tissue damage due to release of a plethora of toxic oxidants and proteases, a cause of acute lung injury (ALI). Despite its clinical importance, the molecular regulation of neutrophil migration is poorly understood. The small GTPase Rap1b is generally viewed as a positive regulator of immune cell functions by controlling bidirectional integrin signaling. However, we found that Rap1b-deficient mice exhibited enhanced neutrophil recruitment to inflamed lungs and enhanced susceptibility to endotoxin shock. Unexpectedly, Rap1b deficiency promoted the transcellular route of diapedesis through endothelial cell. Increased transcellular migration of Rap1b-deficient neutrophils in vitro was selectively mediated by enhanced PI3K-Akt activation and invadopodia-like protrusions. Akt inhibition in vivo suppressed excessive Rap1b-deficient neutrophil migration and associated endotoxin shock. The inhibitory action of Rap1b on PI3K signaling may be mediated by activation of phosphatase SHP-1. Thus, this study reveals an unexpected role for Rap1b as a key suppressor of neutrophil migration and lung inflammation.
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Research Foundation, Cincinnati, OH 45229 University of Cincinnati College of Medicine, Cincinnati OH 45229.
authors.forename: Sachin
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Research Foundation, Cincinnati, OH 45229 University of Cincinnati College of Medicine, Cincinnati OH 45229.
authors.forename: Juying
authors.initials: J
authors.lastname: Xu
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Research Foundation, Cincinnati, OH 45229 University of Cincinnati College of Medicine, Cincinnati OH 45229.
authors.forename: Rupali Sani
authors.initials: RS
authors.lastname: Kumar
authors.affiliation: Blood Research Institute, Blood Center of Wisconsin, Milwaukee, WI 53214.
authors.forename: Sribalaji
authors.initials: S
authors.lastname: Lakshmikanthan
authors.affiliation: Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Cancer Research Institute, Indianapolis, IN 46202.
authors.forename: Reuben
authors.initials: R
authors.lastname: Kapur
authors.affiliation: Division of Developmental Biology, Cincinnati Children's Research Foundation, Cincinnati, OH 45229.
authors.forename: Matthew
authors.initials: M
authors.lastname: Kofron
authors.affiliation: Blood Research Institute, Blood Center of Wisconsin, Milwaukee, WI 53214.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Chrzanowska-Wodnicka
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Research Foundation, Cincinnati, OH 45229 University of Cincinnati College of Medicine, Cincinnati OH 45229 Marie-Dominique.Filippi@cchmc.org.
authors.forename: Marie-Dominique
authors.initials: MD
authors.lastname: Filippi
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D039481:CD11b Antigen / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000276:immunology / Q000502:physiology*; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007154:Immune System Diseases / Q000276:immunology / Q000503:physiopathology; D007960:Leukocyte Disorders / Q000276:immunology / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000276:immunology / Q000502:physiology*; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction; D057705:Transendothelial and Transepithelial Migration / Q000276:immunology / Q000502:physiology; D020668:rap GTP-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: D000199:Actins; D039481:CD11b Antigen; D006575:Heterocyclic Compounds, 3-Ring; C548887:MK 2206; D018129:Phosphatidylinositol Phosphates; C060974:phosphatidylinositol 3,4,5-triphosphate; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; C509248:Ptpn6 protein, mouse; C492136:Rap1b protein, mouse; D020668:rap GTP-Binding Proteins
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