title: Peptidylarginine deiminase inhibition is immunomodulatory and vasculoprotective in murine lupus.
abstract: Recent evidence suggests that enhanced neutrophil extracellular trap (NET) formation activates plasmacytoid dendritic cells and serves as a source of autoantigens in SLE. We propose that aberrant NET formation is also linked to organ damage and to the premature vascular disease characteristic of human SLE. Here, we demonstrate enhanced NET formation in the New Zealand mixed 2328 (NZM) model of murine lupus. NZM mice also developed autoantibodies to NETs as well as the ortholog of human cathelicidin/LL37 (CRAMP), a molecule externalized in the NETs. NZM mice were treated with Cl-amidine, an inhibitor of peptidylarginine deiminases (PAD), to block NET formation and were evaluated for lupus-like disease activity, endothelial function, and prothrombotic phenotype. Cl-amidine treatment inhibited NZM NET formation in vivo and significantly altered circulating autoantibody profiles and complement levels while reducing glomerular IgG deposition. Further, Cl-amidine increased the differentiation capacity of bone marrow endothelial progenitor cells, improved endothelium-dependent vasorelaxation, and markedly delayed time to arterial thrombosis induced by photochemical injury. Overall, these findings suggest that PAD inhibition can modulate phenotypes crucial for lupus pathogenesis and disease activity and may represent an important strategy for mitigating cardiovascular risk in lupus patients.
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109-5680, USA.
authors.forename: Jason S
authors.initials: JS
authors.lastname: Knight
authors.forename: Wenpu
authors.initials: W
authors.lastname: Zhao
authors.forename: Wei
authors.initials: W
authors.lastname: Luo
authors.forename: Venkataraman
authors.initials: V
authors.lastname: Subramanian
authors.forename: Alexander A
authors.initials: AA
authors.lastname: O'Dell
authors.forename: Srilakshmi
authors.initials: S
authors.lastname: Yalavarthi
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Hodgin
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Eitzman
authors.forename: Paul R
authors.initials: PR
authors.lastname: Thompson
authors.forename: Mariana J
authors.initials: MJ
authors.lastname: Kaplan
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000097:blood; D001854:Bone Marrow Cells / Q000502:physiology; D002318:Cardiovascular Diseases / Q000201:enzymology / Q000209:etiology / Q000276:immunology / Q000517:prevention & control*; D002341:Carotid Artery Thrombosis / Q000517:prevention & control; D002454:Cell Differentiation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004727:Endothelium / Q000473:pathology; D005260:Female; D006801:Humans; D006867:Hydrolases / Q000037:antagonists & inhibitors*; D007279:Injections, Subcutaneous; D008180:Lupus Erythematosus, Systemic / Q000150:complications / Q000188:drug therapy / Q000201:enzymology / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology; D009952:Ornithine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D010641:Phenotype; D000076342:Protein-Arginine Deiminases; D013234:Stem Cells / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects
chemical_list: D001323:Autoantibodies; C558727:N-alpha-benzoyl-N5-(2-chloro-1-iminoethyl)-L-ornithine amide; D009952:Ornithine; D006867:Hydrolases; D000076342:Protein-Arginine Deiminases