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. 2011 Jul 28;118(4):1099-108.
doi: 10.1182/blood-2010-12-324756. Epub 2011 May 6.

The RacGAP ArhGAP15 is a master negative regulator of neutrophil functions

Carlotta Costa  1 , Giulia Germena, Erica L Martin-Conte, Ivan Molineris, Eleonora Bosco, Stefano Marengo, Ornella Azzolino, Fiorella Altruda, V Marco Ranieri, Emilio Hirsch
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Free article

The RacGAP ArhGAP15 is a master negative regulator of neutrophil functions

Carlotta Costa et al. Blood. .
Free article

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.

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Comment in

  • Neutrophils bridled by GAPs.
    Kolanus W. Kolanus W. Blood. 2011 Jul 28;118(4):832-4. doi: 10.1182/blood-2011-06-354357. Blood. 2011. PMID: 21799097 No abstract available.

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