Myeloid-Specific Deletion of Peptidylarginine Deiminase 4 Mitigates Atherosclerosis

Frontiers in Immunology
Yudong LiuMariana J Kaplan

Abstract

Increasing evidence suggests that neutrophil extracellular traps (NETs) may play a role in promoting atherosclerotic plaque lesions in humans and in murine models. The exact pathways involved in NET-driven atherogenesis remain to be systematically characterized. To assess the extent to which myeloid-specific peptidylarginine deiminase 4 (PAD4) and PAD4-dependent NET formation contribute to atherosclerosis, mice with myeloid-specific deletion of PAD4 were generated and backcrossed to Apoe-/- mice. The kinetics of atherosclerosis development were determined. NETs, but not macrophage extracellular traps, were present in atherosclerotic lesions as early as 3 weeks after initiating high-fat chow. The presence of NETs was associated with the development of atherosclerosis and with inflammatory responses in the aorta. Specific deletion of PAD4 in the myeloid lineage significantly reduced atherosclerosis burden in association with diminished NET formation and reduced inflammatory responses in the aorta. NETs stimulated macrophages to synthesize inflammatory mediators, including IL-1β, CCL2, CXCL1, and CXCL2. Our data support the notion that NETs promote atherosclerosis and that the use of specific PAD4 inhibitors may have therapeutic b...Continue Reading

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Citations

Feb 21, 2019·Journal of Lipid Research·Alan R Tall, Marit Westerterp
Mar 29, 2019·Cardiovascular Research·Aldo BonaventuraLuca Liberale
Jul 19, 2019·Arteriosclerosis, Thrombosis, and Vascular Biology·Charlotte ThålinHåkan Wallén
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Jan 13, 2021·International Journal of Molecular Sciences·Johannes KlopfChristoph Neumayer
Nov 7, 2020·Clinical Reviews in Allergy & Immunology·Yudong Liu, Mariana J Kaplan
Feb 3, 2021·The Journal of Clinical Investigation·Sarthak Gupta, Mariana J Kaplan
Mar 23, 2021·Frontiers in Immunology·Michele Fresneda AlarconHelen Louise Wright
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Nov 11, 2021·Journal of Leukocyte Biology·Drinalda CelaBorko Amulic

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Methods Mentioned

BETA
lavage
fluorescence-activated cell sorting
confocal microscopy
dissection
FCS
FACS
Flow Cytometry
PCR
ELISA

Software Mentioned

FlowJo
Pro Plus
GraphPad
Image
GraphPad Prism

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