title: The GTPase-activating protein ARAP3 regulates chemotaxis and adhesion-dependent processes in neutrophils.
abstract: Neutrophils form a vital part of the innate immune response, but at the same time their inappropriate activation contributes to autoimmune diseases. Many molecular components are involved in fine-tuning neutrophil function. We report here the first characterization of the role of ARAP3, a PI3K and Rap-regulated GTPase-activating protein for RhoA and Arf6 in murine neutrophils. We show that neutrophils lacking ARAP3 are preactivated in vitro and in vivo, exhibiting increased β2 integrin affinity and avidity. ARAP3-deficient neutrophils are hyperresponsive in several adhesion-dependent situations in vitro, including the formation of reactive oxygen species, adhesion, spreading, and granule release. ARAP3-deficient cells adhere more firmly under flow conditions in vitro and to the vessel wall in vivo. Finally, loss of ARAP3 interferes with integrin-dependent neutrophil chemotaxis. The results of the present study suggest an important function of ARAP3 downstream of Rap. By modulating β2 integrin activity, ARAP3 guards neutrophils in their quiescent state unless activated.
authors.affiliation: Inositide Laboratory, The Babraham Institute, Cambridge, UK.
authors.forename: Laure
authors.initials: L
authors.lastname: Gambardella
authors.forename: Karen E
authors.initials: KE
authors.lastname: Anderson
authors.forename: Claudia
authors.initials: C
authors.lastname: Nussbaum
authors.forename: Anne
authors.initials: A
authors.lastname: Segonds-Pichon
authors.forename: Tânia
authors.initials: T
authors.lastname: Margarido
authors.forename: Laura
authors.initials: L
authors.lastname: Norton
authors.forename: Thomas
authors.initials: T
authors.lastname: Ludwig
authors.forename: Markus
authors.initials: M
authors.lastname: Sperandio
authors.forename: Phillip T
authors.initials: PT
authors.lastname: Hawkins
authors.forename: Len
authors.initials: L
authors.lastname: Stephens
authors.forename: Sonja
authors.initials: S
authors.lastname: Vermeren
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D002634:Chemotaxis, Leukocyte / Q000502:physiology*; D005260:Female; D020690:GTPase-Activating Proteins / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D020690:GTPase-Activating Proteins; D017382:Reactive Oxygen Species