Low Density Lipoprotein Exposure of Plasmacytoid Dendritic Cells Blunts Toll-like Receptor 7/9 Signaling via NUR77

Anette Christ; Pieter G Goossens; Erwin Wijnands; Han Jin; Bart Legein; Tammy Oth; Aaron Isaacs; Monika Stoll; Joris Vanderlocht; Esther Lutgens; Mat J A P Daemen; Martin Zenke; Erik A L Biessen

doi:10.3390/biomedicines10051152

Low Density Lipoprotein Exposure of Plasmacytoid Dendritic Cells Blunts Toll-like Receptor 7/9 Signaling via NUR77

Anette Christ, Pieter G Goossens, Erwin Wijnands, Han Jin, Bart Legein, Tammy Oth, Aaron Isaacs, Monika Stoll, Joris Vanderlocht, Esther Lutgens, Mat J A P Daemen, Martin Zenke, Erik A L Biessen^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

BACKGROUND: Pathogens or trauma-derived danger signals induced maturation and activation of plasmacytoid dendritic cells (pDCs) is a pivotal step in pDC-dependent host defense. Exposure of pDC to cardiometabolic disease-associated lipids and proteins may well influence critical signaling pathways, thereby compromising immune responses against endogenous, bacterial and viral pathogens. In this study, we have addressed if hyperlipidemia impacts human pDC activation, cytokine response and capacity to prime CD4+ T cells.

METHODS AND RESULTS: We show that exposure to pro-atherogenic oxidized low-density lipoproteins (oxLDL) led to pDC lipid accumulation, which in turn ablated a Toll-like receptor (TLR) 7 and 9 dependent up-regulation of pDC maturation markers CD40, CD83, CD86 and HLA-DR. Moreover, oxLDL dampened TLR9 activation induced the production of pro-inflammatory cytokines in a NUR77/IRF7 dependent manner and impaired the capacity of pDCs to prime and polarize CD4+ T helper (Th) cells.

CONCLUSION: Our findings reveal profound effects of dyslipidemia on pDC responses to pathogen-derived signals.

Original language	English
Article number	1152
Number of pages	17
Journal	Biomedicines
Volume	10
Issue number	5
DOIs	https://doi.org/10.3390/biomedicines10051152
Publication status	Published - 17 May 2022

Keywords

ANTIGEN PRESENTATION
ATHEROSCLEROTIC LESIONS
CHEMOKINES
DISEASE
INTERFERON-PRODUCING CELLS
MATURATION
MICE
MIGRATION
VIRUS
cholesterol
dendritic cells
interferon
nuclear receptor
toll like receptors
viral response

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10.3390/biomedicines10051152Licence: CC BY

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Christ, A., Goossens, P. G., Wijnands, E., Jin, H., Legein, B., Oth, T., Isaacs, A., Stoll, M., Vanderlocht, J., Lutgens, E., Daemen, M. J. A. P., Zenke, M., & Biessen, E. A. L. (2022). Low Density Lipoprotein Exposure of Plasmacytoid Dendritic Cells Blunts Toll-like Receptor 7/9 Signaling via NUR77. Biomedicines, 10(5), Article 1152. https://doi.org/10.3390/biomedicines10051152

@article{9a82973b2fbb45f698f2ccc5d88e0ff2,

title = "Low Density Lipoprotein Exposure of Plasmacytoid Dendritic Cells Blunts Toll-like Receptor 7/9 Signaling via NUR77",

abstract = "BACKGROUND: Pathogens or trauma-derived danger signals induced maturation and activation of plasmacytoid dendritic cells (pDCs) is a pivotal step in pDC-dependent host defense. Exposure of pDC to cardiometabolic disease-associated lipids and proteins may well influence critical signaling pathways, thereby compromising immune responses against endogenous, bacterial and viral pathogens. In this study, we have addressed if hyperlipidemia impacts human pDC activation, cytokine response and capacity to prime CD4+ T cells.METHODS AND RESULTS: We show that exposure to pro-atherogenic oxidized low-density lipoproteins (oxLDL) led to pDC lipid accumulation, which in turn ablated a Toll-like receptor (TLR) 7 and 9 dependent up-regulation of pDC maturation markers CD40, CD83, CD86 and HLA-DR. Moreover, oxLDL dampened TLR9 activation induced the production of pro-inflammatory cytokines in a NUR77/IRF7 dependent manner and impaired the capacity of pDCs to prime and polarize CD4+ T helper (Th) cells.CONCLUSION: Our findings reveal profound effects of dyslipidemia on pDC responses to pathogen-derived signals.",

keywords = "ANTIGEN PRESENTATION, ATHEROSCLEROTIC LESIONS, CHEMOKINES, DISEASE, INTERFERON-PRODUCING CELLS, MATURATION, MICE, MIGRATION, VIRUS, cholesterol, dendritic cells, interferon, nuclear receptor, toll like receptors, viral response",

author = "Anette Christ and Goossens, {Pieter G} and Erwin Wijnands and Han Jin and Bart Legein and Tammy Oth and Aaron Isaacs and Monika Stoll and Joris Vanderlocht and Esther Lutgens and Daemen, {Mat J A P} and Martin Zenke and Biessen, {Erik A L}",

note = "Funding Information: Funding: This work was supported by DFG GRK1508 (“Eucar”) (A.C., M.J.A.P.D., M.Z.), by the Boehringer Ingelheim Foundation (A.C.), by Interreg IV “Healthy Ageing” (E.A.L.B.), by ZonMW/FAPESP “DNAMoving” (E.A.L.B.) and by a CARIM research incentive (B.L.). Publisher Copyright: {\textcopyright} 2022 by the authors. Licensee MDPI, Basel, Switzerland.",

year = "2022",

month = may,

day = "17",

doi = "10.3390/biomedicines10051152",

language = "English",

volume = "10",

journal = "Biomedicines",

issn = "2227-9059",

publisher = "MDPI AG",

number = "5",

}

TY - JOUR

T1 - Low Density Lipoprotein Exposure of Plasmacytoid Dendritic Cells Blunts Toll-like Receptor 7/9 Signaling via NUR77

AU - Christ, Anette

AU - Goossens, Pieter G

AU - Wijnands, Erwin

AU - Jin, Han

AU - Legein, Bart

AU - Oth, Tammy

AU - Isaacs, Aaron

AU - Stoll, Monika

AU - Vanderlocht, Joris

AU - Lutgens, Esther

AU - Daemen, Mat J A P

AU - Zenke, Martin

AU - Biessen, Erik A L

N1 - Funding Information: Funding: This work was supported by DFG GRK1508 (“Eucar”) (A.C., M.J.A.P.D., M.Z.), by the Boehringer Ingelheim Foundation (A.C.), by Interreg IV “Healthy Ageing” (E.A.L.B.), by ZonMW/FAPESP “DNAMoving” (E.A.L.B.) and by a CARIM research incentive (B.L.). Publisher Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland.

PY - 2022/5/17

Y1 - 2022/5/17

N2 - BACKGROUND: Pathogens or trauma-derived danger signals induced maturation and activation of plasmacytoid dendritic cells (pDCs) is a pivotal step in pDC-dependent host defense. Exposure of pDC to cardiometabolic disease-associated lipids and proteins may well influence critical signaling pathways, thereby compromising immune responses against endogenous, bacterial and viral pathogens. In this study, we have addressed if hyperlipidemia impacts human pDC activation, cytokine response and capacity to prime CD4+ T cells.METHODS AND RESULTS: We show that exposure to pro-atherogenic oxidized low-density lipoproteins (oxLDL) led to pDC lipid accumulation, which in turn ablated a Toll-like receptor (TLR) 7 and 9 dependent up-regulation of pDC maturation markers CD40, CD83, CD86 and HLA-DR. Moreover, oxLDL dampened TLR9 activation induced the production of pro-inflammatory cytokines in a NUR77/IRF7 dependent manner and impaired the capacity of pDCs to prime and polarize CD4+ T helper (Th) cells.CONCLUSION: Our findings reveal profound effects of dyslipidemia on pDC responses to pathogen-derived signals.

AB - BACKGROUND: Pathogens or trauma-derived danger signals induced maturation and activation of plasmacytoid dendritic cells (pDCs) is a pivotal step in pDC-dependent host defense. Exposure of pDC to cardiometabolic disease-associated lipids and proteins may well influence critical signaling pathways, thereby compromising immune responses against endogenous, bacterial and viral pathogens. In this study, we have addressed if hyperlipidemia impacts human pDC activation, cytokine response and capacity to prime CD4+ T cells.METHODS AND RESULTS: We show that exposure to pro-atherogenic oxidized low-density lipoproteins (oxLDL) led to pDC lipid accumulation, which in turn ablated a Toll-like receptor (TLR) 7 and 9 dependent up-regulation of pDC maturation markers CD40, CD83, CD86 and HLA-DR. Moreover, oxLDL dampened TLR9 activation induced the production of pro-inflammatory cytokines in a NUR77/IRF7 dependent manner and impaired the capacity of pDCs to prime and polarize CD4+ T helper (Th) cells.CONCLUSION: Our findings reveal profound effects of dyslipidemia on pDC responses to pathogen-derived signals.

KW - ANTIGEN PRESENTATION

KW - ATHEROSCLEROTIC LESIONS

KW - CHEMOKINES

KW - DISEASE

KW - INTERFERON-PRODUCING CELLS

KW - MATURATION

KW - MICE

KW - MIGRATION

KW - VIRUS

KW - cholesterol

KW - dendritic cells

KW - interferon

KW - nuclear receptor

KW - toll like receptors

KW - viral response

U2 - 10.3390/biomedicines10051152

DO - 10.3390/biomedicines10051152

M3 - Article

C2 - 35625889

SN - 2227-9059

VL - 10

JO - Biomedicines

JF - Biomedicines

IS - 5

M1 - 1152

ER -

Low Density Lipoprotein Exposure of Plasmacytoid Dendritic Cells Blunts Toll-like Receptor 7/9 Signaling via NUR77

Abstract

Keywords

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