The NADPH oxidase Nox2 regulates VEGFR1/CSF-1R-mediated microglial chemotaxis and promotes early postnatal infiltration of phagocytes in the subventricular zone of the mouse cerebral cortex

Authors

  • Aurélia Lelli,

    1. University Pierre et Marie Curie-Paris 6, Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière, Paris, France
    2. Inserm U975, Paris, France
    3. CNRS, UMR 7225, Paris, France
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  • Annie Gervais,

    1. University Pierre et Marie Curie-Paris 6, Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière, Paris, France
    2. Inserm U975, Paris, France
    3. CNRS, UMR 7225, Paris, France
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  • Catherine Colin,

    1. University Pierre et Marie Curie-Paris 6, Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière, Paris, France
    2. Inserm U975, Paris, France
    3. CNRS, UMR 7225, Paris, France
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  • Cyril Chéret,

    1. University Pierre et Marie Curie-Paris 6, Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière, Paris, France
    2. Inserm U975, Paris, France
    3. CNRS, UMR 7225, Paris, France
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  • Carmen Ruiz de Almodovar,

    1. Laboratory of Angiogenesis and the Neurovascular Link, The Vesalius Research Center, VIB and K.U.Leuven, Campus Gasthuiberg, B3000-Leuven, Belgium
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  • Peter Carmeliet,

    1. Laboratory of Angiogenesis and the Neurovascular Link, The Vesalius Research Center, VIB and K.U.Leuven, Campus Gasthuiberg, B3000-Leuven, Belgium
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  • Karl-Heinz Krause,

    1. Department of Pathology and Immunology, University of Geneva, Centre Medical Universitaire, CH-1211 Geneva 4, Switzerland
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  • Séverine Boillée,

    1. University Pierre et Marie Curie-Paris 6, Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière, Paris, France
    2. Inserm U975, Paris, France
    3. CNRS, UMR 7225, Paris, France
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  • Michel Mallat

    1. University Pierre et Marie Curie-Paris 6, Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière, Paris, France
    2. Inserm U975, Paris, France
    3. CNRS, UMR 7225, Paris, France
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Address correspondence to Michel Mallat, Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière, Inserm/UMR_S975, CNRS UMR 7225; Hôpital de la Salpêtrière, 47 boulevard de l'Hôpital, 75013 Paris, France. E-mail: michel.mallat@upmc.fr

ABSTRACT

The phagocyte NADPH oxidase Nox2 generates superoxide ions implicated in the elimination of microorganisms and the redox control of inflammatory signaling. However, the role of Nox2 in phagocyte functions unrelated to immunity or pathologies is unknown. During development, oriented cell migrations insure the timely recruitment and function of phagocytes in developing tissues. Here, we have addressed the role of Nox2 in the directional migration of microglial cells during development. We show that microglial Nox2 regulates the chemotaxis of purified microglia mediated by the colony stimulating factor-1 receptor (CSF-1R) and the vascular endothelial growth factor receptor-1 (VEGFR1). Stimulation of these receptors triggers activation of Nox2 at the leading edge of polarized cells. In the early postnatal stages of mouse brain development, Nox2 is activated in macrophages / microglial cells in the lateral ventricle or the adjacent subventricular zone (SVZ). Fluorescent microglia injected into the lateral ventricle infiltrate the dorso-caudal SVZ through a mechanism that is blocked by pretreatment of the injected cells with an irreversible Nox inhibitor. Infiltration of endogenous microglia into the caudal SVZ of the cerebral cortex is prevented by (1) Nox2 gene deficiency, (2) treatment with a Nox2 inhibitor (apocynin), and (3) invalidation of the VEGFR1 kinase. We conclude that phagocytes move out of the lateral ventricle soon after birth and infiltrate the cortical SVZ through a mechanism requiring microglial Nox2 and VEGFR1 activation. Nox2 therefore modulates the migration of microglia and their development.

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