title: The RacGAP ArhGAP15 is a master negative regulator of neutrophil functions.
abstract: In phagocytes, GTPases of the Rac family control crucial antimicrobial functions. The RacGAP ArhGAP15 negatively modulates Rac activity in leukocytes, but its in vivo role in innate immunity remains largely unknown. Here we show that neutrophils and macrophages derived from mice lacking ArhGAP15 presented higher Rac activity but distinct phenotypes. In macrophages, the loss of ArhGAP15 induced increased cellular elongation and membrane protrusions but did not modify chemotactic responses. Conversely, the lack of ArhGAP15 in neutrophils affected critical Rac-dependent antimicrobial functions, specifically causing enhanced chemotactic responses, straighter directional migration, amplified reactive oxygen species production, increased phagocytosis, and improved bacterial killing. In vivo, in a model of severe abdominal sepsis, these effects contributed to increase neutrophil recruitment to the site of infection, thereby limiting bacterial growth, controlling infection spread, reducing systemic inflammation, and ultimately improving survival in ArhGAP15-null mice. Altogether, these results demonstrate the relevance of ArhGAP15 in the selective regulation of multiple neutrophil functions, suggesting that ArhGAP15 targeting might be beneficial in specific pathologic settings like severe sepsis.
authors.affiliation: Department of Genetic, Biology and Biochemistry, University of Torino, Torino, Italy.
authors.forename: Carlotta
authors.initials: C
authors.lastname: Costa
authors.forename: Giulia
authors.initials: G
authors.lastname: Germena
authors.forename: Erica L
authors.initials: EL
authors.lastname: Martin-Conte
authors.forename: Ivan
authors.initials: I
authors.lastname: Molineris
authors.forename: Eleonora
authors.initials: E
authors.lastname: Bosco
authors.forename: Stefano
authors.initials: S
authors.lastname: Marengo
authors.forename: Ornella
authors.initials: O
authors.lastname: Azzolino
authors.forename: Fiorella
authors.initials: F
authors.lastname: Altruda
authors.forename: V Marco
authors.initials: VM
authors.lastname: Ranieri
authors.forename: Emilio
authors.initials: E
authors.lastname: Hirsch
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002469:Cell Separation; D002634:Chemotaxis, Leukocyte / Q000502:physiology; D005434:Flow Cytometry; D020690:GTPase-Activating Proteins / Q000276:immunology* / Q000378:metabolism; D007150:Immunohistochemistry; D008264:Macrophages / Q000201:enzymology / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000276:immunology*; D009504:Neutrophils / Q000201:enzymology* / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018805:Sepsis / Q000276:immunology*
chemical_list: D020690:GTPase-Activating Proteins