title: Peptidylarginine deiminase inhibition disrupts NET formation and protects against kidney, skin and vascular disease in lupus-prone MRL/lpr mice.
abstract: OBJECTIVE
  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.
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Jason S
authors.initials: JS
authors.lastname: Knight
authors.affiliation: Department of Chemistry, The Scripps Research Institute, Jupiter, Florida, USA.
authors.forename: Venkataraman
authors.initials: V
authors.lastname: Subramanian
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Alexander A
authors.initials: AA
authors.lastname: O'Dell
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Srilakshmi
authors.initials: S
authors.lastname: Yalavarthi
authors.affiliation: Systemic Autoimmunity Branch, Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Wenpu
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Systemic Autoimmunity Branch, Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Carolyne K
authors.initials: CK
authors.lastname: Smith
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Hodgin
authors.affiliation: Department of Chemistry, The Scripps Research Institute, Jupiter, Florida, USA.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Thompson
authors.affiliation: Systemic Autoimmunity Branch, Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Mariana J
authors.initials: MJ
authors.lastname: Kaplan
mesh_terms: D000578:Amidines / Q000494:pharmacology*; D000818:Animals; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D065206:Extracellular Traps / Q000378:metabolism*; D006867:Hydrolases / Q000037:antagonists & inhibitors*; D007674:Kidney Diseases / Q000209:etiology / Q000517:prevention & control*; D008180:Lupus Erythematosus, Systemic / Q000150:complications / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D019463:Mice, Inbred MRL lpr; D000076342:Protein-Arginine Deiminases; D014652:Vascular Diseases / Q000209:etiology / Q000517:prevention & control*
chemical_list: D000578:Amidines; D006867:Hydrolases; D000076342:Protein-Arginine Deiminases
keywords: Autoimmune Diseases; Autoimmunity; Systemic Lupus Erythematosus
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