Peptidylarginine Deiminase Inhibition Mitigates NET Formation and Protects Against Kidney, Skin, and Vascular Disease in Lupus-Prone MRL/Lpr Mice

Jason S. Knight¹, Venkataraman Subramanian², Alexander A. O'Dell¹, Srilakshmi Yalavarthi¹, Wenpu Zhao³, Carolyne K. Smith³, Jeffrey B. Hodgin⁴, Paul Thompson² and Mariana J. Kaplan³, ¹Department of Internal Medicine, Division of Rheumatology, University of Michigan, Ann Arbor, MI, ²The Scripps Research Institute, Jupiter, FL, ³Systemic Autoimmunity Branch, Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, ⁴Department of Pathology, University of Michigan, Ann Arbor, MI

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: cutaneous lupus, interferons, Nephritis and systemic lupus erythematosus (SLE), Neutrophil Extracellular Traps

Session Information

Title: Systemic Lupus Erythematosus - Animal Models

Session Type: Abstract Submissions (ACR)

Background/Purpose: An imbalance between neutrophil extracellular trap (NET) production and NET degradation has been observed in systemic lupus erythematosus (SLE), potentially contributing to autoantigen externalization, type I interferon production, and endothelial dysfunction. We have previously demonstrated that peptidylarginine deiminase (PAD) inhibition can mitigate NET formation and protect against vascular damage in the New Zealand Mixed model of lupus. However, another strategy for disrupting NET formation—knockout of NOX2—accelerates lupus in a different mouse model, MRL/lpr. Here, we tested PAD inhibition in MRL/lpr mice in an attempt to clarify whether some NET inhibitory pathways may be consistently therapeutic across different models of SLE.

Methods: NET formation, autoantibodies to NETs, interferon signature, and endothelial function were characterized at baseline in MRL/lpr mice. MRL/lpr mice were also treated for six weeks (daily, from 8 to 14 weeks of age) with two different PAD inhibitors, Cl-amidine and the newly developed BB-Cl-amidine. NET formation, interferon signature, endothelial function, nephritis, and skin disease were examined in treated mice.

Results: Neutrophils from MRL/lpr mice demonstrate more NET formation than controls. MRL/lpr mice also form autoantibodies to NETs and have evidence of endothelial dysfunction. PAD inhibition with either Cl-amidine or BB-Cl-amidine markedly improves endothelial function, while downregulating expression of type I interferon-regulated genes. PAD inhibition also protects against proteinuria, immune complex deposition in the kidneys, and skin disease.

Conclusion: Chemical PAD inhibition reduces NET formation, while protecting against damage to the endothelium, kidneys, and skin in various lupus models. The strategy by which NETs are targeted will have to be carefully considered if human studies are to be undertaken.

Disclosure:

J. S. Knight,
None;

V. Subramanian,
None;

A. A. O’Dell,
None;

S. Yalavarthi,
None;

W. Zhao,
None;

C. K. Smith,
None;

J. B. Hodgin,
None;

P. Thompson,
None;

M. J. Kaplan,
None.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/peptidylarginine-deiminase-inhibition-mitigates-net-formation-and-protects-against-kidney-skin-and-vascular-disease-in-lupus-prone-mrllpr-mice/