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Anti-myeloperoxidase antibodies attenuate the monocyte response to LPS and shape macrophage development
Reena J. Popat, … , Claudia Kemper, Michael G. Robson
Reena J. Popat, … , Claudia Kemper, Michael G. Robson
Published January 26, 2017
Citation Information: JCI Insight. ;2(2):e87379. https://doi.org/10.1172/jci.insight.87379.
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Research Article Inflammation

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

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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

Reena J. Popat, Seran Hakki, Alpesh Thakker, Alice M. Coughlan, Julie Watson, Mark A. Little, Corinne M. Spickett, Paul Lavender, Behdad Afzali, Claudia Kemper, Michael G. Robson

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Figure 6

MPO-ANCA causes an increase in monocyte survival and differentiation to macrophages by increasing CSF-1 expression.

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MPO-ANCA causes an increase in monocyte survival and differentiation to ...
(A) Number of cells remaining after culturing peripheral blood monocytes with 10% human type AB serum and anti-myeloperoxidase antibodies (MPO-ANCA) (n = 10) or control IgG for 6 days (n = 10) without LPS. Results are shown for 2 healthy monocyte donors. (B) CSF-1 gene expression in peripheral blood monocytes after 18 hours in culture MPO-ANCA or control IgG, with and without the MPO inhibitor AZD5904 (400 nM). (C) The effect of varying concentrations of the CSF-1 receptor inhibitor GW280 on cell number in the presence of MPO-ANCA (n = 2) or control IgG (n = 2). (D) The effect of the MPO inhibitor AZD5904 (400 nM) on cell number after peripheral blood monocytes were cultured for 6 days in 10% AB serum in the presence of MPO-ANCA (n = 3) or control IgG (n = 3). (E) The effect of TLR2/4 blockade on cell number after 6 days in 10% AB serum in the presence of MPO-ANCA (n = 3) or control IgG (n = 3). *P < 0.05, ***P < 0.001 by 2-tailed Student’s t test. Error bars represent mean ± SEM. For a given monocyte donor, n is the number of IgG preparations from different individuals. They are not technical replicates or repeated measures of the same IgG samples.

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