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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 4

MPO-ANCA inhibits TLR signaling pathways.

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MPO-ANCA inhibits TLR signaling pathways.
(A) The effect of exogenous IL...
(A) The effect of exogenous IL-6 on IL-10 secretion from peripheral blood monocytes incubated for 18 hours with LPS and anti-myeloperoxidase antibodies (MPO-ANCA) (n = 2) or control IgG (n = 2). NA, not activated (no LPS). All other groups contained LPS in addition to the stated type of IgG preparation. (B) Volcano plot comparing monocytes activated for 6 hours with either MPO-ANCA (n = 3) or control IgG (n = 3) in the presence of LPS. Threshold for significance is 1.75-fold change in either direction and P < 0.05. The 566 differentially expressed transcripts are highlighted in orange (listed in Supplemental Table 2). (C and D) Gene Ontology (C) and KEGG pathway (D) functional annotation analysis of the differentially expressed genes, showing the top 6 terms for each. (E) Gene set enrichment analysis (GSEA) for enrichment of genes in the KEGG TLR signaling pathway between MPO-ANCA–treated and control IgG–treated monocytes. (F) Heat map of the core-enriched genes from the GSEA in E. NES, normalized enrichment score; FDR, false discovery rate. In panel A, 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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