Elimination of Granulocytic Myeloid‐Derived Suppressor Cells in Lupus‐Prone Mice Linked to Reactive Oxygen Species–Dependent Extracellular Trap Formation

Abstract

Objective. Emerging evidence supports a crucial role of myeloid-derived suppressor cells (MDSCs) in the regulation of autoimmune diseases. However, their role in systemic lupus erythematosus (SLE) remains unknown. This study sought to address the role of MDSCs in the pathogenesis of SLE.Methods. MDSCs from (NZB 3 NZW)F1 lupusprone mice were assessed for phenotype by flow cytometry, and the function of MDSCs was analyzed by in vitro T cell proliferation assay and real-time quantitative polymerase chain reaction. Extracellular trap (ET) formation was evaluated by immunofluorescence and confocal microscopy. The production of reactive oxygen species (ROS) by Ly-6G1 cells was determined by fluorescenceactivated cell sorting analysis.Results. Expansion of MDSCs was impaired and the function of MDSCs was defective in the lymphoid organs of (NZB 3 NZW)F1 lupus-prone mice with established disease, in which involvement of predominantly the granulocytic MDSC (G-MDSC) cell subset was observed. More specifically, the results showed that increased elimination of G-MDSCs, driven by the inflammatory milieu of lupus, could be attributed to ET formation, and that cytokines, such as interferon-a (IFNa), IFNg, and interleukin-6, play a role in this process. Induction of ET release by G-MDSCs was mediated by the production of ROS, since inhibition of ROS generation significantly reduced ET release.Conclusion. Collectively, the results of this study reveal that elimination of a crucial regulatory immune cell subset is a feature of the SLE microenvironment. These findings provide new insights into the pathogenetic mechanisms of the disease.Although the incidence of autoimmune diseases is individually rare, these diseases affect ;5% of the population in Western countries. Systemic lupus erythematosus (SLE) is the prototypic systemic autoimmune disease, characterized by involvement of multiple organs (1). The development of SLE and its progression have been attributed to the interplay between innate immune components and self-reactive B and T lymphocytes and their products (2). Despite major advancements in elucidating the pathways underlying the effector phases of

Neutrophil extracellular traps exacerbate Th1‐mediated autoimmune responses in rheumatoid arthritis by promoting DC maturation

“…Finally, in mice, the presence of proinflammatory cytokines such as IL‐6 and TNF‐α, which are abundant in CIA sera , might influence NET formation upon PMN signaling. This is in line with our recent report in lupus‐prone mice that IL‐6 demonstrated to drive NET release by granulocytic cells .…”

“…Although it is becoming apparent that NETs have a significant impact on chronic autoimmune inflammatory diseases such as lupus, psoriasis, atherosclerosis, and arthritis , the mechanism involved in NET‐mediated adaptive autoimmune responses remains elusive. Herein, we provide new insights into the NETs‐mediated induction of T‐cell autoreactivity that contribute to the immunopathogenesis of RA.…”

Lupus Skin Is Primed for IL-6 Inflammatory Responses through a Keratinocyte-Mediated Autocrine Type I Interferon Loop

“…Murine studies support a role for IL-6 in both the MRL/ lpr and Junb epidermal deletion models of cutaneous lupus (Cash et al, 2010; Pflegerl et al, 2009). Some have identified the importance of IL-6 in promotion of neutrophil extracellular trap formation (Vlachou et al, 2016); this phenomenon has been noted to be important in murine cutaneous lupus. A chart review performed on cutaneous lupus skin samples from our RT-PCR and immunohistochemistry data revealed a significant correlation between IL-6 levels in the skin and SS-A antibody status.…”

Inducible nitric oxide synthase and systemic lupus erythematosus: a systematic review and meta-analysis

“…Although the present analysis showed a positive correlation between iNOS and SLE, the source of iNOS is unknown. Recently, increasing evidence has suggested that proportions of myeloid-derived suppressor cells (MDSCs), a heterogeneous myeloid precursor, enhanced in SLE patients and mice [38,39]. Although a variety of potential mechanisms is involved in the immunosuppressive function of MDSCs, the main suppressive activity of MDSCs is associated with the secretion of arginase-1 and iNOS [30,40].…”