TY - JOUR
T1 - The GTPase-activating protein ARAP3 regulates chemotaxis and adhesion-dependent processes in neutrophils
AU - Gambardella, Laure
AU - Anderson, Karen E
AU - Nussbaum, Claudia
AU - Segonds-Pichon, Anne
AU - Margarido, Tânia
AU - Norton, Laura
AU - Ludwig, Thomas
AU - Sperandio, Markus
AU - Hawkins, Phillip T
AU - Stephens, Len
AU - Vermeren, Sonja
PY - 2011
Y1 - 2011
N2 - 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.
AB - 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.
U2 - 10.1182/blood-2010-10-312959
DO - 10.1182/blood-2010-10-312959
M3 - Article
C2 - 21490342
SN - 1528-0020
VL - 118
SP - 1087
EP - 1098
JO - Blood
JF - Blood
IS - 4
ER -