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

Glia. 2013 Sep;61(9):1542-55. doi: 10.1002/glia.22540. Epub 2013 Jul 8.

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.

Keywords: colony stimulating factor-1; microglia; vascular endothelial growth factor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetophenones / pharmacology
  • Actins / genetics
  • Animals
  • Animals, Newborn
  • Antigens, Differentiation / metabolism
  • Bromodeoxyuridine
  • CD11b Antigen / metabolism
  • Cell Movement / genetics
  • Cells, Cultured
  • Cerebral Cortex / anatomy & histology
  • Chemotaxis / genetics
  • Chemotaxis / physiology*
  • Chickens
  • Enzyme Inhibitors / pharmacology
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism*
  • Lateral Ventricles / cytology*
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Microglia / metabolism*
  • NADPH Oxidase 2
  • NADPH Oxidases / genetics
  • NADPH Oxidases / metabolism*
  • Nuclear Proteins / metabolism
  • Phagocytes / metabolism*
  • Signal Transduction
  • Vascular Endothelial Growth Factor Receptor-1 / genetics
  • Vascular Endothelial Growth Factor Receptor-1 / metabolism*

Substances

  • Acetophenones
  • Actins
  • Antigens, Differentiation
  • CD11b Antigen
  • Enzyme Inhibitors
  • Membrane Glycoproteins
  • Nuclear Proteins
  • enhanced green fluorescent protein
  • monocyte-macrophage differentiation antigen
  • Green Fluorescent Proteins
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • acetovanillone
  • Cybb protein, mouse
  • NADPH Oxidase 2
  • NADPH Oxidases
  • Vascular Endothelial Growth Factor Receptor-1
  • Bromodeoxyuridine