Peptidylarginine deiminase inhibition is immunomodulatory and vasculoprotective in murine lupus.
Authors
Knight, Jason S.Zhao, Wenpu
Luo, Wei
Subramanian, Venkataraman
O'Dell, Alexander A.
Yalavarthi, Srilakshmi
Hodgin, Jeffrey B.
Eitzman, Daniel T.
Thompson, Paul R
Kaplan, Mariana J.
UMass Chan Affiliations
Department of Biochemistry and Molecular PharmacologyDocument Type
Journal ArticlePublication Date
2013-07-01Keywords
AnimalsAutoantibodies
Bone Marrow Cells
Cardiovascular Diseases
Carotid Artery Thrombosis
Cell Differentiation
Cells, Cultured
Disease Models, Animal
Endothelium
Female
Humans
Hydrolases
Injections, Subcutaneous
Lupus Erythematosus, Systemic
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Neutrophils
Ornithine
Phenotype
Stem Cells
Vasodilation
Biochemistry
Enzymes and Coenzymes
Medicinal-Pharmaceutical Chemistry
Therapeutics
Metadata
Show full item recordAbstract
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.Source
J Clin Invest. 2013 Jul;123(7):2981-93. doi: 10.1172/JCI67390. Epub 2013 Jun 3. Link to article on publisher's siteDOI
10.1172/JCI67390Permanent Link to this Item
http://hdl.handle.net/20.500.14038/50014Notes
At the time of publication, Paul Thompson was not yet affiliated with UMass Medical School.
Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1172/JCI67390