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Peptidylarginine deiminase inhibition disrupts NET formation and protects against kidney, skin and vascular disease in lupus-prone MRL/lpr mice
Open accessAbstract
Objectives An imbalance between neutrophil extracellular trap (NET) formation and degradation has been described in systemic lupus erythematosus (SLE), potentially contributing to autoantigen externalisation, type I interferon synthesis and endothelial damage. We have demonstrated that peptidylarginine deiminase (PAD) inhibition reduces NET formation and protects against lupus-related vascular damage in the New Zealand Mixed model of lupus. However, another strategy for inhibiting NETs--knockout of NOX2--accelerates lupus in a different murine model, MRL/lpr. Here, we test the effects of PAD inhibition on MRL/lpr mice in order to clarify whether some NET inhibitory pathways may be consistently therapeutic across models of SLE.Methods NET formation and autoantibodies to NETs were characterised in lupus-prone MRL/lpr mice. MRL/lpr mice were also treated with two different PAD inhibitors, Cl-amidine and the newly described BB-Cl-amidine. NET formation, endothelial function, interferon signature, nephritis and skin disease were examined in treated mice.Results Neutrophils from MRL/lpr mice demonstrate accelerated NET formation compared with controls. MRL/lpr mice also form autoantibodies to NETs and have evidence of endothelial dysfunction. PAD inhibition markedly improves endothelial function, while downregulating the expression of type I interferon-regulated genes. PAD inhibition also reduces proteinuria and immune complex deposition in the kidneys, while protecting against skin disease.Conclusions PAD inhibition reduces NET formation, while protecting against lupus-related damage to the vasculature, kidneys and skin in various lupus models. The strategy by which NETs are inhibited will have to be carefully considered if human studies are to be undertaken.
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“Commercially available PAD4 inhibitors have serum half-lives of ∼15 min-4 h (37, 38).”
From Cancer cells induce metastasis-supporting neutrophil extracellular DNA traps (2016) · cites this paper as [37]
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Metadata
- Authors
- Knight, J. S., Subramanian, V., O'Dell, A. A., Yalavarthi, S., Zhao, W., Smith, C. K., Hodgin, J. B., Thompson, P. R., & Kaplan, M. J.
- Affiliations
- University of Michigan (US)
- Scripps Research Institute (US)
- National Institutes of Health (US)
- Corresponding author
- Kaplan, Mariana J
- Venue
- Annals of the Rheumatic Diseases
- Publisher
- Elsevier BV
- Published
- 2015-12
- Volume
- 74
- Issue
- 12
- Pages
- 2199-2206
- ISSN
- 0003-4967 (ISSN-L)
- PMC
- PMC4320672
- OpenAlex
- W2159514587
- Cited by
- 443
- References
- 53
- Citations by year
- 2026: 31 · 2025: 34 · 2024: 42 · 2023: 40 · 2022: 50 · 2021: 44 · 2020: 33 · 2019: 46 · 2018: 43 · 2017: 30 · 2016: 30 · 2015: 20
- FWCI
- 22.16
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Annals of the Rheumatic Diseases (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- The Journal of the American Medical Association (JAMA) Network (American Medical Association) (submittedVersion)
- Funders
- National Institutes of Health (Z99 AR999999)
- National Heart, Lung, and Blood Institute (HL088419, R01HL088419)
- National Cancer Institute (R01CA151304, CA151304)
- National Institute of General Medical Sciences (R01GM079357, GM 079357)
- Topics
- Health Sciences › Medicine › Rheumatology › Systemic Lupus Erythematosus Research
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Health Sciences › Medicine › Rheumatology › Vasculitis and related conditions
- Keywords
- neutrophil extracellular traps, systemic lupus erythematosus, MRL/lpr mice, endothelial dysfunction, type I interferon, nephritis, proteinuria, immune complex deposition, skin diseases, vascular injury, Cl-amidine
- MeSH terms
- Protein-Arginine Deiminases, Amidines, Animals, Disease Models, Animal, Enzyme-Linked Immunosorbent Assay, Hydrolases, Kidney Diseases, Lupus Erythematosus, Systemic, Vascular Diseases, Mice, Inbred MRL lpr, Mice, Extracellular Traps
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