SIRPα controls the activity of the phagocyte NADPH oxidase by restricting the expression of gp91(phox)

Cell Rep. 2012 Oct 25;2(4):748-55. doi: 10.1016/j.celrep.2012.08.027. Epub 2012 Sep 27.

Abstract

The phagocyte NADPH oxidase mediates oxidative microbial killing in granulocytes and macrophages. However, because the reactive oxygen species produced by the NADPH oxidase can also be toxic to the host, it is essential to control its activity. Little is known about the endogenous mechanism(s) that limits NADPH oxidase activity. Here, we demonstrate that the myeloid-inhibitory receptor SIRPα acts as a negative regulator of the phagocyte NADPH oxidase. Phagocytes isolated from SIRPα mutant mice were shown to have an enhanced respiratory burst. Furthermore, overexpression of SIRPα in human myeloid cells prevented respiratory burst activation. The inhibitory effect required interactions between SIRPα and its natural ligand, CD47, as well as signaling through the SIRPα cytoplasmic immunoreceptor tyrosine-based inhibitory motifs. Suppression of the respiratory burst by SIRPα was caused by a selective repression of gp91(phox) expression, the catalytic component of the phagocyte NADPH oxidase complex. Thus, SIRPα can limit gp91(phox) expression during myeloid development, thereby controlling the magnitude of the respiratory burst in phagocytes.

MeSH terms

  • Animals
  • CD47 Antigen / metabolism
  • Cell Differentiation
  • Cell Line
  • Gene Expression Regulation*
  • Granulocytes / immunology
  • Granulocytes / metabolism
  • Humans
  • Macrophages / immunology
  • Macrophages / metabolism
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mutation
  • Myeloid Cells / metabolism
  • NADPH Oxidase 2
  • NADPH Oxidases / genetics
  • NADPH Oxidases / metabolism*
  • Phagocytes / enzymology*
  • Phagocytosis
  • Reactive Oxygen Species / metabolism
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / metabolism*
  • Respiratory Burst
  • Signal Transduction

Substances

  • CD47 Antigen
  • Membrane Glycoproteins
  • Ptpns1 protein, mouse
  • Reactive Oxygen Species
  • Receptors, Immunologic
  • Cybb protein, mouse
  • NADPH Oxidase 2
  • NADPH Oxidases