title: Neutrophils Regulate Humoral Autoimmunity by Restricting Interferon-γ Production via the Generation of Reactive Oxygen Species.
abstract: Here, we examine the mechanism by which plasmacytoid dendritic cells (pDCs) and type I interferons promote humoral autoimmunity. In an amyloid-induced experimental autoimmune model, neutrophil depletion enhanced anti-nuclear antibody development, which correlated with heightened IFN-γ production by natural killer (NK) cells. IFN-α/β produced by pDCs activated NK cells via IL-15 induction. Neutrophils released reactive oxygen species (ROS), which negatively modulated the levels of IL-15, thereby inhibiting IFN-γ production. Mice deficient in NADPH oxidase 2 produced increased amounts of IFN-γ and developed augmented titers of autoantibodies. Both the pDC-IFN-α/β pathway and IFN-γ were indispensable in stimulating humoral autoimmunity. Male NZB/W F1 mice expressed higher levels of superoxide than their female lupus-prone siblings, and depletion of neutrophils resulted in spontaneous NK cell and autoimmune B cell activation. Our findings suggest a regulatory role for neutrophils in vivo and highlight the importance of an NK-IFN-γ axis downstream of the pDC-IFN-α/β pathway in systemic autoimmunity.
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Rheumatology, Renji Hospital, Shanghai Institute of Rheumatology, Shanghai Jiao Tong University School of Medicine, Shanghai 200001, China.
authors.forename: Xinfang
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; The University of Texas Graduate School of Biomedical Sciences, Houston, TX 77030, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Dorta-Estremera
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Di Domizio
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; The University of Texas Graduate School of Biomedical Sciences, Houston, TX 77030, USA.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Anthony
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; The University of Texas Graduate School of Biomedical Sciences, Houston, TX 77030, USA.
authors.forename: Stephanie S
authors.initials: SS
authors.lastname: Watowich
authors.affiliation: Department of Dermatology, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Popkin
authors.affiliation: MedImmune, LLC, Gaithersburg, MD 20878, USA.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Liu
authors.affiliation: MedImmune, LLC, Gaithersburg, MD 20878, USA.
authors.forename: Philip
authors.initials: P
authors.lastname: Brohawn
authors.affiliation: MedImmune, LLC, Gaithersburg, MD 20878, USA.
authors.forename: Yihong
authors.initials: Y
authors.lastname: Yao
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; The University of Texas Graduate School of Biomedical Sciences, Houston, TX 77030, USA.
authors.forename: Kimberly S
authors.initials: KS
authors.lastname: Schluns
authors.affiliation: Department of Microbiology and Immunology and Cancer Research Institute, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Lewis L
authors.initials: LL
authors.lastname: Lanier
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; The University of Texas Graduate School of Biomedical Sciences, Houston, TX 77030, USA. Electronic address: wei.cao.phd@gmail.com.
authors.forename: Wei
authors.initials: W
authors.lastname: Cao
mesh_terms: D000818:Animals; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D056724:Immunity, Humoral; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism*; D019409:Interleukin-15 / Q000235:genetics / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000276:immunology*; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D019409:Interleukin-15; D017382:Reactive Oxygen Species; D007371:Interferon-gamma