Highlight Publication August 2011

Gambardella L, Anderson KE, Nussbaum C, Segonds-Pichon A, Margarido T, Norton L, Ludwig T, Sperandio M, Hawkins PT, Stephens LR, Vermeren S.
The GTPase-activating protein ARAP3 regulates chemotaxis and adhesion-dependent processes in neutrophils.
Blood. 118 (4):1087-98
http://dx.doi.org/10.1182/blood-2010-10-312959

Lay description:

Neutrophils form part of the non-specific immune system. They are constantly generated in the bone marrow and, once mature, reside in the blood. In the case of an insult, they are the first immune cells to become activated. They stop circulating and instead adhere to the blood vessel wall, then exit through it into the tissue and migrate to the site of insult by a process called chemotaxis. They produce reactive oxygen species, release granules containing cytotoxic molecules and phagocytose bacteria. Proper control of neutrophil activity is therefore vital; insufficient neutrophil activity causes immunodeficiency characterised by recurrent bacterial infections while overly active neutrophils cause excessive inflammation as exemplified by some autoimmune diseases.

We analysed neutrophils lacking a protein called ARAP3, which regulates cross-talk between several key regulators of intracellular signalling proteins called PI3Kinase, Rap, Rho and Arf. Our work uncovered a likely role for ARAP3 in the control of neutrophil activity. Neutrophils lacking ARAP3 were too ‘sticky’, since their main integrins (molecules required for cell adhesion) were pre-activated. Cell lacking ARAP3 produced too much reactive oxygen species and cytotoxic enzymes when their integrins were activated by adhesion; their ability to migrate in an integrin-dependent fashion was also affected. Adhesion-dependent processes were already known to be controlled by Rap, one of ARAP3’s regulators. This work suggests an important role for ARAP3 downstream of Rap in the neutrophil, helping to guard the cells in a basal state unless there is an activating signal.

About the lead authors

Karen Anderson obtained her PhD in inositol phosphate signalling in heart tissue at the University of Melbourne, Australia. She did her first post-doc investigating the role of PI3Kinase lipids in platelet signalling at the Department of Medicine in Box Hill, Australia. She joined the Inositide Laboratory at the Babraham Institute, headed by Len Stephens and Phill Hawkins, in 1997, investigating PI3Kinase signalling in neutrophils. Afterwards she was the awarded the inaugural Australian National Health and Medical Research Council C.J. Martin/R.G Menzies fellowship for two years, extending her stay until 2001 on a Beit Fellowship. After a little time back in Australia on a R.D. Wright fellowship, Karen returned to the Inositide Laboratory at Babraham in 2004 to continue research on PI3Kinase and its lipid products in neutrophils and other cells. In 2004, she was made a Senior Research Associate.

Laure Gambardella holds a PhD in Molecular & Cellular Biology of Development from the Pierre et Marie Curie University, Paris, awarded for her work with Yann Barrandon on transcription factors in epidermal stem cells. She obtained a post-doctoral position in the Department of Hematology, University of Cambridge led by Anthony Green, working on hematopoietic stem cells, erythopoiesis and angiogenesis. Back in the laboratory of Yann Barrandon in Paris and then in Lausanne, Laure supervised projects developing in vivo and in vitro models to follow stem cell migration inside hair follicles using retroviral infection and confocal microscopy. She joined Martin Turner’s group at the Babraham Institute in 2004 and applied the technique of retroviral infection to hematopoietic stem cells. Since 2008 Laure has been working in the Inositide Laboratory analysing the function of the GTPase activating protein ARAP3 in angiogenesis and neutrophils.