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

Xinfang Huang; Jingjing Li; Stephanie Dorta-Estremera; Jeremy Di Domizio; Scott M Anthony; Stephanie S Watowich; Daniel Popkin; Zheng Liu; Philip Brohawn; Yihong Yao; Kimberly S Schluns; Lewis L Lanier; Wei Cao

doi:10.1016/j.celrep.2015.07.021

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

Journal article

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

Xinfang Huang, Jingjing Li, Stephanie Dorta-Estremera, Jeremy Di Domizio, Scott M Anthony, Stephanie S Watowich, Daniel Popkin, Zheng Liu, Philip Brohawn, Yihong Yao, …

Cell reports (Cambridge), Vol.12(7), pp.1120-1132

08/18/2015

DOI: 10.1016/j.celrep.2015.07.021

PMCID: PMC4545388

PMID: 26257170

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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.

Autoimmunity

Animals

B-Lymphocytes - immunology

Dendritic Cells - immunology

Female

Immunity, Humoral

Interferon-gamma - genetics

Interferon-gamma - metabolism

Interleukin-15 - genetics

Interleukin-15 - metabolism

Killer Cells, Natural - immunology

Lupus Erythematosus, Systemic - immunology

Male

Mice

Mice, Inbred BALB C

Mice, Inbred C57BL

Neutrophils - immunology

Reactive Oxygen Species - metabolism

Details

Title: Subtitle: Neutrophils Regulate Humoral Autoimmunity by Restricting Interferon-γ Production via the Generation of Reactive Oxygen Species
Creators: Xinfang Huang - Shanghai Jiao Tong University
Jingjing Li - The University of Texas MD Anderson Cancer Center
Stephanie Dorta-Estremera - The University of Texas MD Anderson Cancer Center
Jeremy Di Domizio - The University of Texas MD Anderson Cancer Center
Scott M Anthony - The University of Texas at Austin
Stephanie S Watowich - The University of Texas at Austin
Daniel Popkin - Case Western Reserve University
Zheng Liu - MedImmune
Philip Brohawn - MedImmune
Yihong Yao - MedImmune
Kimberly S Schluns - The University of Texas at Austin
Lewis L Lanier - University of California, San Francisco
Wei Cao - The University of Texas at Austin
Resource Type: Journal article
Publication Details: Cell reports (Cambridge), Vol.12(7), pp.1120-1132
DOI: 10.1016/j.celrep.2015.07.021
PMID: 26257170
PMCID: PMC4545388
ISSN: 2211-1247
eISSN: 2211-1247
Grant note: AI074809 / NIAID NIH HHS P30 CA016672 / NCI NIH HHS R01 AI068129 / NIAID NIH HHS R01 AI074809 / NIAID NIH HHS AI068129 / NIAID NIH HHS CA016672 / NCI NIH HHS
Language: English
Date published: 08/18/2015
Academic Unit: Pathology
Record Identifier: 9984185277902771

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