title: A Reduction in Intracellular Reactive Oxygen Species Due to a Mutation in NCF4 Promotes Autoimmune Arthritis in Mice.
abstract: The mechanisms linking deficits in the phagocytic NADPH oxidase 2 (NOX2) complex to autoimmunity are so far incompletely understood. Deficiency in neutrophil cytosolic factor 1 (NCF1) inactivates the NOX2 complex, leading to a dramatic reduction of intra- and extracellular reactive oxygen species (ROS) and enhanced susceptibility to autoimmune disease. The contribution of intracellular NOX2 activity to autoimmune regulation is, however, unknown. Another component of the NOX2 complex, NCF4, directs the NOX2 complex to phagosomal membranes via binding to phosphatidylinositol 3-phosphate (PtdIns3P) and has been proposed to regulate intracellular ROS levels. To address the impact of NCF4 and selective changes in intracellular ROS production on autoimmune inflammation, we studied collagen-induced arthritis (CIA) and mannan-induced psoriatic arthritis-like disease (MIP) in mice lacking NCF4 and mice with a mutation in the PtdIns3P-binding site of NCF4.
  
  
  
  Targeted deletion of Ncf4 (Ncf4-/-) led to severe defects in overall ROS production due to concomitant reduction of NCF2 and NCF1. These mice displayed delayed neutrophil apoptosis and enhanced innate immune responses, and they developed aggravated CIA and MIP. Disruption of the PtdIns3P-binding site by targeted mutation (Ncf4*/*) resulted in selective defects in intracellular NOX2 activity, which entailed milder effects on innate immunity and MIP but clearly promoted susceptibility to CIA. Innovation and Conclusion: This is, to our knowledge, the first study addressing the development of autoimmunity in an organism with selectively compromised NOX2-dependent intracellular ROS levels. Our data reveal a specific role for NCF4-mediated intracellular ROS production in regulating autoimmunity and chronic inflammation. Antioxid. Redox Signal. 25, 983-996.
authors.affiliation: Division of Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institute , Stockholm, Sweden .
authors.forename: Susann
authors.initials: S
authors.lastname: Winter
authors.affiliation: Division of Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institute , Stockholm, Sweden .
authors.forename: Malin
authors.initials: M
authors.lastname: Hultqvist Hopkins
authors.affiliation: Division of Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institute , Stockholm, Sweden .
authors.forename: Frida
authors.initials: F
authors.lastname: Laulund
authors.affiliation: Division of Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institute , Stockholm, Sweden .
authors.forename: Rikard
authors.initials: R
authors.lastname: Holmdahl
mesh_terms: D000818:Animals; D017209:Apoptosis; D001168:Arthritis / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D001169:Arthritis, Experimental; D001327:Autoimmune Diseases / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D007113:Immunity, Innate; D018836:Inflammation Mediators / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D008562:Membrane Glycoproteins; D010750:Phosphoproteins; D017382:Reactive Oxygen Species; C085072:neutrophil cytosol factor 40K; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases
keywords: NOX2 complex; Ncf4; arthritis; autoimmunity; p40phox; reactive oxygen species