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Cell Rep. 2015 Aug 18;12(7):1120-32. doi: 10.1016/j.celrep.2015.07.021. Epub 2015 Aug 6.

Neutrophils Regulate Humoral Autoimmunity by Restricting Interferon-γ Production via the Generation of Reactive Oxygen Species.

Author information

1
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.
2
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
3
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.
4
Department of Dermatology, Case Western Reserve University, Cleveland, OH 44106, USA.
5
MedImmune, LLC, Gaithersburg, MD 20878, USA.
6
Department of Microbiology and Immunology and Cancer Research Institute, University of California, San Francisco, San Francisco, CA 94143, USA.
7
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.

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.

PMID:
26257170
PMCID:
PMC4545388
DOI:
10.1016/j.celrep.2015.07.021
[Indexed for MEDLINE]
Free PMC Article

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