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

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

Research output: Contribution to journalArticle

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.

LanguageEnglish
Article numbere87379
JournalJCI Insight
Volume2
Issue number2
DOIs
Publication statusPublished - 26 Jan 2017

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Antineutrophil Cytoplasmic Antibodies
Peroxidase
Monocytes
Anti-Idiotypic Antibodies
Macrophages
Interleukin-10
Transforming Growth Factor beta
Autoantibodies
Interleukin-6
Neutrophils
Myeloblastin
T-Lymphocytes
Macrophage Colony-Stimulating Factor
Fc Receptors
Vasculitis
Phospholipids
Fibrosis
Anti-Inflammatory Agents
Immunoglobulin G
Inflammation

Bibliographical note

Copyright © 2017 Popat et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Cite this

Popat, R. J., Hakki, S., Thakker, A., Coughlan, A. M., Watson, J., Little, M. A., ... Robson, M. G. (2017). Anti-myeloperoxidase antibodies attenuate the monocyte response to LPS and shape macrophage development. 2(2), [e87379]. https://doi.org/10.1172/jci.insight.87379
Popat, Reena J. ; Hakki, Seran ; Thakker, Alpesh ; Coughlan, Alice M. ; Watson, Julie ; Little, Mark A. ; Spickett, Corinne M. ; Lavender, Paul ; Afzali, Behdad ; Kemper, Claudia ; Robson, Michael G. / Anti-myeloperoxidase antibodies attenuate the monocyte response to LPS and shape macrophage development. 2017 ; Vol. 2, No. 2.
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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.",
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Popat, RJ, Hakki, S, Thakker, A, Coughlan, AM, Watson, J, Little, MA, Spickett, CM, Lavender, P, Afzali, B, Kemper, C & Robson, MG 2017, 'Anti-myeloperoxidase antibodies attenuate the monocyte response to LPS and shape macrophage development' vol. 2, no. 2, e87379. https://doi.org/10.1172/jci.insight.87379

Anti-myeloperoxidase antibodies attenuate the monocyte response to LPS and shape macrophage development. / Popat, Reena J.; Hakki, Seran; Thakker, Alpesh; Coughlan, Alice M.; Watson, Julie; Little, Mark A.; Spickett, Corinne M.; Lavender, Paul; Afzali, Behdad; Kemper, Claudia; Robson, Michael G.

Vol. 2, No. 2, e87379, 26.01.2017.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Anti-myeloperoxidase antibodies attenuate the monocyte response to LPS and shape macrophage development

AU - Popat, Reena J.

AU - Hakki, Seran

AU - Thakker, Alpesh

AU - Coughlan, Alice M.

AU - Watson, Julie

AU - Little, Mark A.

AU - Spickett, Corinne M.

AU - Lavender, Paul

AU - Afzali, Behdad

AU - Kemper, Claudia

AU - Robson, Michael G.

N1 - Copyright © 2017 Popat et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

PY - 2017/1/26

Y1 - 2017/1/26

N2 - 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.

AB - 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.

U2 - 10.1172/jci.insight.87379

DO - 10.1172/jci.insight.87379

M3 - Article

VL - 2

IS - 2

M1 - e87379

ER -

Popat RJ, Hakki S, Thakker A, Coughlan AM, Watson J, Little MA et al. Anti-myeloperoxidase antibodies attenuate the monocyte response to LPS and shape macrophage development. 2017 Jan 26;2(2). e87379. https://doi.org/10.1172/jci.insight.87379