title: Anti-myeloperoxidase antibodies attenuate the monocyte response to LPS and shape macrophage development.
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.
authors.affiliation: Division of Transplant Immunology and Mucosal Biology, MRC Centre for Transplantation, King's College London, Guy's Hospital, Great Maze Pond, London, United Kingdom.
authors.forename: Reena J
authors.initials: RJ
authors.lastname: Popat
authors.affiliation: Division of Transplant Immunology and Mucosal Biology, MRC Centre for Transplantation, King's College London, Guy's Hospital, Great Maze Pond, London, United Kingdom.
authors.forename: Seran
authors.initials: S
authors.lastname: Hakki
authors.affiliation: School of Life & Health Sciences, Aston University, Aston Triangle, Birmingham, United Kingdom.
authors.forename: Alpesh
authors.initials: A
authors.lastname: Thakker
authors.affiliation: Trinity Health Kidney Centre, Department of Clinical Medicine, Trinity College Dublin, St. James' Hospital Campus, Dublin, Ireland.
authors.forename: Alice M
authors.initials: AM
authors.lastname: Coughlan
authors.affiliation: MRC and Asthma UK Centre in Allergic Mechanisms of Asthma, King's College London, Guy's Hospital, Great Maze Pond, London, United Kingdom.
authors.forename: Julie
authors.initials: J
authors.lastname: Watson
authors.affiliation: Trinity Health Kidney Centre, Department of Clinical Medicine, Trinity College Dublin, St. James' Hospital Campus, Dublin, Ireland.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Little
authors.affiliation: School of Life & Health Sciences, Aston University, Aston Triangle, Birmingham, United Kingdom.
authors.forename: Corinne M
authors.initials: CM
authors.lastname: Spickett
authors.affiliation: MRC and Asthma UK Centre in Allergic Mechanisms of Asthma, King's College London, Guy's Hospital, Great Maze Pond, London, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: Lavender
authors.affiliation: Division of Transplant Immunology and Mucosal Biology, MRC Centre for Transplantation, King's College London, Guy's Hospital, Great Maze Pond, London, United Kingdom.
authors.forename: Behdad
authors.initials: B
authors.lastname: Afzali
authors.affiliation: Division of Transplant Immunology and Mucosal Biology, MRC Centre for Transplantation, King's College London, Guy's Hospital, Great Maze Pond, London, United Kingdom.
authors.forename: Claudia
authors.initials: C
authors.lastname: Kemper
authors.affiliation: Division of Transplant Immunology and Mucosal Biology, MRC Centre for Transplantation, King's College London, Guy's Hospital, Great Maze Pond, London, United Kingdom.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Robson
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D056648:Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis / Q000276:immunology* / Q000378:metabolism; D019268:Antibodies, Antineutrophil Cytoplasmic; D001323:Autoantibodies / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002470:Cell Survival; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology*; D016753:Interleukin-10 / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D038041:Lymphopoiesis; D016173:Macrophage Colony-Stimulating Factor / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D010084:Oxidation-Reduction; D009195:Peroxidase / Q000276:immunology* / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism; D011961:Receptors, Fc; D051193:Toll-Like Receptors / Q000276:immunology / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000378:metabolism
chemical_list: D019268:Antibodies, Antineutrophil Cytoplasmic; D001323:Autoantibodies; C000628668:CSF1 protein, human; C508609:IL10 protein, human; C508600:IL6 protein, human; D007074:Immunoglobulin G; D015850:Interleukin-6; D008070:Lipopolysaccharides; D010743:Phospholipids; D011961:Receptors, Fc; D051193:Toll-Like Receptors; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D016173:Macrophage Colony-Stimulating Factor; D009195:Peroxidase