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Neutrophils regulate humoral autoimmunity by restricting interferon gamma production via the generation of reactive oxygen species (BA7P.142)


 The mechanism by which plasmacytoid dendritic cells (pDCs) promote humoral autoimmunity is unclear. In amyloid-induced experimental autoimmune model, pDC activation is accompanied by prominent neutrophilia. We investigated the contribution of neutrophils since neutrophils have been critically implicated in the pathogenesis of systemic autoimmunity. Unexpectedly, neutrophil depletion enhanced anti-nuclear antibody development, which was correlated with heightened IFN-γ production by natural killer (NK) cells. IFN-α/β produced by pDCs activated NK cells via the induction of IL-15. Neutrophils released reactive oxygen species (ROS), which negatively modulated the levels of IL-15, thereby inhibiting IFN-γ production. Consistently, mice deficient of NADPH oxidase 2 (Nox2) 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 mice had 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 reveal a regulatory role of neutrophils in vivo and highlight the importance of IFN-γ downstream of the pDC-IFN-α/β pathway in systemic autoimmunity.