Jason S Knight1, Venkataraman Subramanian2, Alexander A O'Dell1, Srilakshmi Yalavarthi1, Wenpu Zhao3, Carolyne K Smith3, Jeffrey B Hodgin4, Paul R Thompson2, Mariana J Kaplan3. 1. Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA. 2. Department of Chemistry, The Scripps Research Institute, Jupiter, Florida, USA. 3. Systemic Autoimmunity Branch, Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA. 4. Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
Abstract
OBJECTIVES: 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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
OBJECTIVES: 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/lprmice 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/lprmice. MRL/lprmice 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/lprmice demonstrate accelerated NET formation compared with controls. MRL/lprmice 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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
Authors: Eneida Villanueva; Srilakshmi Yalavarthi; Celine C Berthier; Jeffrey B Hodgin; Ritika Khandpur; Andrew M Lin; Cory J Rubin; Wenpu Zhao; Stephen H Olsen; Matthew Klinker; David Shealy; Michael F Denny; Joel Plumas; Laurence Chaperot; Matthias Kretzler; Allen T Bruce; Mariana J Kaplan Journal: J Immunol Date: 2011-05-25 Impact factor: 5.422
Authors: Alexander A Chumanevich; Corey P Causey; Bryan A Knuckley; Justin E Jones; Deepak Poudyal; Alena P Chumanevich; Tia Davis; Lydia E Matesic; Paul R Thompson; Lorne J Hofseth Journal: Am J Physiol Gastrointest Liver Physiol Date: 2011-03-17 Impact factor: 4.052
Authors: Kevin L Bicker; Lynne Anguish; Alexander A Chumanevich; Michael D Cameron; Xiangli Cui; Erin Witalison; Venkataraman Subramanian; Xuesen Zhang; Alena P Chumanevich; Lorne J Hofseth; Scott A Coonrod; Paul R Thompson Journal: ACS Med Chem Lett Date: 2012-10-26 Impact factor: 4.345
Authors: B S Andrews; R A Eisenberg; A N Theofilopoulos; S Izui; C B Wilson; P J McConahey; E D Murphy; J B Roths; F J Dixon Journal: J Exp Med Date: 1978-11-01 Impact factor: 14.307
Authors: Gail J Gardiner; Sarah N Deffit; Shawna McLetchie; Liliana Pérez; Crystal C Walline; Janice S Blum Journal: Front Immunol Date: 2013-09-23 Impact factor: 7.561
Authors: Rachael A Gordon; Jan M Herter; Florencia Rosetti; Allison M Campbell; Hiroshi Nishi; Michael Kashgarian; Sheldon I Bastacky; Anthony Marinov; Kevin M Nickerson; Tanya N Mayadas; Mark J Shlomchik Journal: JCI Insight Date: 2017-05-18
Authors: He Meng; Srilakshmi Yalavarthi; Yogendra Kanthi; Levi F Mazza; Megan A Elfline; Catherine E Luke; David J Pinsky; Peter K Henke; Jason S Knight Journal: Arthritis Rheumatol Date: 2017-03 Impact factor: 10.995