Peptidylarginine Deiminase Inhibition Prevents Neutrophil Extracellular Trap Formation, Modulates Innate Immune Responses, and Reduces Vascular Damage In Mice

Jason S. Knight¹, Wei Luo², Alexander A. O'Dell¹, Wenpu Zhao³, Venkataraman Subramanian⁴, Chiao Guo², Robert C. Grenn³, Paul Ryan Thompson⁴, Daniel T. Eitzman² and Mariana J. Kaplan⁵, ¹Department of Internal Medicine, Division of Rheumatology, University of Michigan, Ann Arbor, MI, ²University of Michigan Cardiology, Ann Arbor, MI, ³University of Michigan Rheumatology, Ann Arbor, MI, ⁴The Scripps Research Institute, Jupiter, FL, ⁵Systemic Autoimmunity Branch, National Institutes of Health/NIAMS, Bethesda, MD

Meeting: 2013 ACR/ARHP Annual Meeting

Keywords: Atherosclerosis, innate immunity and interferons, Neutrophil Extracellular Traps

Session Information

Title: Innate Immunity and Rheumatic Disease

Session Type: Abstract Submissions (ACR)

Background/Purpose: Neutrophil extracellular trap (NET) formation promotes vascular damage, while stimulating interferon alpha (IFN-α) production in diseased arteries. Patients with rheumatoid arthritis and systemic lupus erythematosus have evidence of exaggerated NET formation, and suffer from a propensity toward accelerated atherosclerosis. Peptidylarginine deiminase (PAD) inhibition is a strategy that can decrease in vivo NET formation. We tested whether PAD inhibition can inhibit innate immune responses and reduce vascular damage in murine models of atherosclerosis.

Methods: Apoe^-/-mice were treated for 10 weeks with daily injections of Cl-amidine, a PAD inhibitor. Innate immune responses including NET release and IFN-α production were characterized, as was anti-NET autoantibody formation. Degree of atherosclerosis and time to carotid artery thrombosis were also determined.

Results: In Apoe^-/- mice, we found evidence of accelerated NET formation, enhanced IFN-α production in diseased arteries, and autoantibody formation to components of NETs. Further, PAD inhibition blocked NET formation, reduced atherosclerotic lesion area, and delayed time to carotid artery thrombosis in a photochemical injury model. Decreases in atherosclerosis burden were accompanied by reduced recruitment of netting neutrophils and macrophages to arteries, as well as by reduced arterial IFN-α expression.

Conclusion: A pharmacologic intervention that blocks NET formation can reduce atherosclerosis burden in murine systems. These results support a role for aberrant NET formation in the pathogenesis of atherosclerosis through modulation of innate immune responses, with implications for the accelerated atherosclerosis of rheumatoid arthritis and systemic lupus erythematosus.

Disclosure:

J. S. Knight,
None;

W. Luo,
None;

A. A. O’Dell,
None;

W. Zhao,
None;

V. Subramanian,
None;

C. Guo,
None;

R. C. Grenn,
None;

P. R. Thompson,
None;

D. T. Eitzman,
None;

M. J. Kaplan,
None.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/peptidylarginine-deiminase-inhibition-prevents-neutrophil-extracellular-trap-formation-modulates-innate-immune-responses-and-reduces-vascular-damage-in-mice/