Anti-myeloperoxidase antibodies attenuate the monocyte response to LPS and shape macrophage development

JCI Insight. 2017 Jan 26;2(2):e87379. doi: 10.1172/jci.insight.87379.

Abstract

Anti-neutrophil cytoplasmic antibody (ANCA) vasculitis is characterized by the presence of autoantibodies to myeloperoxidase and proteinase-3, which bind monocytes in addition to neutrophils. While a pathological effect on neutrophils is acknowledged, the impact of ANCA on monocyte function is less well understood. Using IgG from patients we investigated the effect of these autoantibodies on monocytes and found that anti-myeloperoxidase antibodies (MPO-ANCA) reduced both IL-10 and IL-6 secretion in response to LPS. This reduction in IL-10 and IL-6 depended on Fc receptors and enzymatic myeloperoxidase and was accompanied by a significant reduction in TLR-driven signaling pathways. Aligning with changes in TLR signals, oxidized phospholipids, which function as TLR4 antagonists, were increased in monocytes in the presence of MPO-ANCA. We further observed that MPO-ANCA increased monocyte survival and differentiation to macrophages by stimulating CSF-1 production. However, this was independent of myeloperoxidase enzymatic activity and TLR signaling. Macrophages differentiated in the presence of MPO-ANCA secreted more TGF-β and further promoted the development of IL-10- and TGF-β-secreting CD4+ T cells. Thus, MPO-ANCA may promote inflammation by reducing the secretion of antiinflammatory IL-10 from monocytes, and MPO-ANCA can alter the development of macrophages and T cells to potentially promote fibrosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis / immunology*
  • Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis / metabolism
  • Antibodies, Antineutrophil Cytoplasmic
  • Autoantibodies / immunology*
  • CD4-Positive T-Lymphocytes / immunology
  • Cell Survival
  • Cells, Cultured
  • Female
  • Humans
  • Immunoglobulin G / immunology*
  • Interleukin-10 / immunology
  • Interleukin-10 / metabolism
  • Interleukin-6 / immunology
  • Interleukin-6 / metabolism
  • Lipopolysaccharides / pharmacology*
  • Lymphopoiesis
  • Macrophage Colony-Stimulating Factor / immunology
  • Macrophage Colony-Stimulating Factor / metabolism
  • Macrophages / drug effects*
  • Macrophages / immunology
  • Macrophages / metabolism
  • Male
  • Middle Aged
  • Monocytes / drug effects*
  • Monocytes / immunology
  • Monocytes / metabolism
  • Oxidation-Reduction
  • Peroxidase / immunology*
  • Peroxidase / metabolism
  • Phospholipids / metabolism
  • Receptors, Fc
  • Toll-Like Receptors / immunology
  • Toll-Like Receptors / metabolism
  • Transforming Growth Factor beta / immunology
  • Transforming Growth Factor beta / metabolism

Substances

  • Antibodies, Antineutrophil Cytoplasmic
  • Autoantibodies
  • CSF1 protein, human
  • IL10 protein, human
  • IL6 protein, human
  • Immunoglobulin G
  • Interleukin-6
  • Lipopolysaccharides
  • Phospholipids
  • Receptors, Fc
  • Toll-Like Receptors
  • Transforming Growth Factor beta
  • Interleukin-10
  • Macrophage Colony-Stimulating Factor
  • Peroxidase