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

Abstract

Summary 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 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 pDC-IFN-α/β pathway in systemic autoimmunity.

Neutrophils Slow Disease Progression in Murine Lupus via Modulation of Autoreactive Germinal Centers

“…Although neutrophils have been shown to act in an immunosuppressive capacity during chronic inflammatory conditions such as malignancy or viral infection, the possibility that a pro-resolving or protective neutrophil is present in lupus has only recently been proposed (15, 16, 36–39). In an amyloid-induced lupus model neutrophil depletion worsened disease similar to our findings.…”

“…In an amyloid-induced lupus model neutrophil depletion worsened disease similar to our findings. A regulatory effect for neutrophils was suggested to be mediated by ROS inhibition of NK cell IFNγ production at local sites of inflammation (15). Another study demonstrated that Gr-1 hi CD11b + splenocytes suppress lupus pathogenesis in young male but not female NZB/W mice based on the finding that administration of anti-Gr-1 antibody in vivo increased anti-dsDNA antibody titers (16).…”

“…In an amyloid-induced model of systemic autoimmunity, neutrophil production of reactive oxygen species (ROS) mediates suppression of systemic IFNγ levels and auto-antibody production (15). Additionally, in vitro co-culture of splenic neutrophils with B lymphocytes isolated from the NZB/W lupus model demonstrated that neutrophils can suppress B cell immunoglobulin production.…”

Neutrophils in animal models of autoimmune disease

“…The most direct experimental evidence of a role for neutrophils in driving systemic autoimmunity comes from chronic neutrophil depletion experiments [13, 14]. Coquery et al found that neutrophil depletion, achieved by every other day injection of the anti-Ly6G depleting mAb for four weeks, led to a reduction in auto-antibody titers, serum IFNγ, serum BAFF, T cell activation as well as the number of splenic germinal center B cells and plasma cells in the autoimmune prone B6.Fas lpr /J Tnfrsf17 −/− strain.…”

“…The regulatory mechanisms utilized by neutrophils includes direct effects, via the production of cytokines such as IL-1, IL-6, IL-10 (in murine neutrophils only), TNF and BAFF that affect other immune cells, as well as indirect effects, through production of superoxides or consumption of nutrients (amino acids or even oxygen) that limit function of neighboring immune cells [13, 14]. Both stimulatory and inhibitory roles for neutrophils, based on their ability to produce various cytokines or indirectly affect other immune cells, have been described in a variety of autoimmune or autoinflammatory processes.…”