SIRPα Controls the Activity of the Phagocyte NADPH Oxidase by Restricting the Expression of gp91phox
Ellen M. van Beek,
Julian Alvarez Zarate,
Robin van Bruggen,
Karin Schornagel,
Anton T.J. Tool,
Takashi Matozaki,
Georg Kraal,
Dirk Roos,
Timo K. van den Berg
Affiliations
Ellen M. van Beek
Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, 1066 CX, Amsterdam, The Netherlands
Julian Alvarez Zarate
Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, 1066 CX, Amsterdam, The Netherlands
Robin van Bruggen
Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, 1066 CX, Amsterdam, The Netherlands
Karin Schornagel
Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, 1066 CX, Amsterdam, The Netherlands
Anton T.J. Tool
Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, 1066 CX, Amsterdam, The Netherlands
Takashi Matozaki
Division of Molecular and Cellular Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
Georg Kraal
Department of Molecular Cell Biology and Immunology, VU Medical Center, 1081 BT, Amsterdam, The Netherlands
Dirk Roos
Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, 1066 CX, Amsterdam, The Netherlands
Timo K. van den Berg
Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, 1066 CX, Amsterdam, The Netherlands
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 gp91phox expression, the catalytic component of the phagocyte NADPH oxidase complex. Thus, SIRPα can limit gp91phox expression during myeloid development, thereby controlling the magnitude of the respiratory burst in phagocytes.
