SIRPα Controls the Activity of the Phagocyte NADPH Oxidase by Restricting the Expression of gp91phox

SummaryThe 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.

Graphical AbstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Activity of the phagocyte NADPH oxidase is restricted by SIRPα ► This involves SIRP-CD47 interactions and signaling through the SIRPα immunoreceptor tyrosine-based inhibitory motifs ► SIRPα signaling represses expression of the catalytic NADPH oxidase subunit gp91phox