title: SIRPα controls the activity of the phagocyte NADPH oxidase by restricting the expression of gp91(phox).
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.
authors.affiliation: Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, 1066 CX, Amsterdam, The Netherlands.
authors.forename: Ellen M
authors.initials: EM
authors.lastname: van Beek
authors.forename: Julian Alvarez
authors.initials: JA
authors.lastname: Zarate
authors.forename: Robin
authors.initials: R
authors.lastname: van Bruggen
authors.forename: Karin
authors.initials: K
authors.lastname: Schornagel
authors.forename: Anton T J
authors.initials: AT
authors.lastname: Tool
authors.forename: Takashi
authors.initials: T
authors.lastname: Matozaki
authors.forename: Georg
authors.initials: G
authors.lastname: Kraal
authors.forename: Dirk
authors.initials: D
authors.lastname: Roos
authors.forename: Timo K
authors.initials: TK
authors.lastname: van den Berg
mesh_terms: D000818:Animals; D051928:CD47 Antigen / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D005786:Gene Expression Regulation; D006098:Granulocytes / Q000276:immunology / Q000378:metabolism; D006801:Humans; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D022423:Myeloid Cells / Q000378:metabolism; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism*; D010586:Phagocytes / Q000201:enzymology*; D010587:Phagocytosis; D017382:Reactive Oxygen Species / Q000378:metabolism; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D016897:Respiratory Burst; D015398:Signal Transduction
chemical_list: D051928:CD47 Antigen; D008562:Membrane Glycoproteins; C501922:Sirpa protein, mouse; D017382:Reactive Oxygen Species; D011971:Receptors, Immunologic; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases