NOX2 mediates quiescent handling of dead cell remnants in phagocytes

Hahn J, Euler M, Kilgus E, Kienhöfer D, Stoof J, Knopf J, Hahn M, Harrer T, Hultqvist M, Olofsson P, Mokhir A, Holmdahl R, Herrmann M, Schett G, Munoz LE, Hoffmann M (2019)


Publication Type: Journal article

Publication year: 2019

Journal

Book Volume: 26

Article Number: 101279

DOI: 10.1016/j.redox.2019.101279

Abstract

The phagocyte NADPH oxidase (the NOX2 complex) generates superoxide, the precursor to reactive oxygen species (ROS). ROS possess both antimicrobial and immunoregulatory function. Inactivating mutations in alleles of the NOX2 complex cause chronic granulomatous disease (CGD), characterized by an enhanced susceptibility to infections and autoimmune diseases such as Systemic lupus erythematosus (SLE). The latter is characterized by insufficient removal of dead cells, resulting in an autoimmune response against components of the cell's nucleus when non-cleared apoptotic cells lose their membrane integrity and present autoantigenic molecules in an inflammatory context. Here we aimed to shed light on the role of the NOX2 complex in handling of secondary necrotic cells (SNECs) and associated consequences for inflammation and autoimmunity during lupus. We show that individuals with SLE and CGD display accumulation of SNECs in blood monocytes and neutrophils. In a CGD phenotypic mouse strain (Ncf1** mice) build-up of SNECs in Ly6CHI blood monocytes was connected with a delayed degradation of the phagosomal cargo and accompanied by production of inflammatory mediators. Treatment with H2O2 or activators of ROS-formation reconstituted phagosomal abundance of SNECs to normal levels. Induction of experimental lupus further induced increased antibody-dependent uptake of SNECs into neutrophils. Lupus-primed Ncf1** neutrophils took up more SNECs than wild type neutrophils, whereas SNEC-accumulation in regulatory Ly6C−/LO monocytes was lower in Ncf1**mice. We deduce that the inflammatory rerouting of immune-stimulatory necrotic material into inflammatory phagocyte subsets contributes to the connection between low ROS production by the NOX2 complex and SLE.

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APA:

Hahn, J., Euler, M., Kilgus, E., Kienhöfer, D., Stoof, J., Knopf, J.,... Hoffmann, M. (2019). NOX2 mediates quiescent handling of dead cell remnants in phagocytes. Redox Biology, 26. https://dx.doi.org/10.1016/j.redox.2019.101279

MLA:

Hahn, Jonas, et al. "NOX2 mediates quiescent handling of dead cell remnants in phagocytes." Redox Biology 26 (2019).

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