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Peptidylarginine deiminase inhibition is immunomodulatory and vasculoprotective in murine lupus
Jason S. Knight, … , Paul R. Thompson, Mariana J. Kaplan
Jason S. Knight, … , Paul R. Thompson, Mariana J. Kaplan
Published June 3, 2013
Citation Information: J Clin Invest. 2013;123(7):2981-2993. https://doi.org/10.1172/JCI67390.
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Research Article Immunology Article has an altmetric score of 11

Peptidylarginine deiminase inhibition is immunomodulatory and vasculoprotective in murine lupus

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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

Jason S. Knight, Wenpu Zhao, Wei Luo, Venkataraman Subramanian, Alexander A. O’Dell, Srilakshmi Yalavarthi, Jeffrey B. Hodgin, Daniel T. Eitzman, Paul R. Thompson, Mariana J. Kaplan

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Figure 3

PAD inhibition blocks NZM NET formation in vitro.

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PAD inhibition blocks NZM NET formation in vitro.
(A) Cl-amidine treatme...
(A) Cl-amidine treatment inhibits histone H3 citrullination. NZM bone marrow neutrophils were treated with 100 nM PMA in the presence or absence of 200 μM Cl-amidine. Whole-cell lysates were resolved by SDS-PAGE. A Western blot representative of 3 independent experiments is shown. H3-Cit, citrullinated histone H3. (B) Cl-amidine treatment inhibits NET formation. NZM neutrophils were treated with PMA in the presence or absence of Cl-amidine for 12 hours. NET formation was determined by fluorescence microscopy. (C) BALB/c neutrophils were incubated with either 2% BALB/c or NZM serum from mice older than 24 weeks for 12 hours in the presence or absence of Cl-amidine, as indicated in parentheses. (D) Cl-amidine treatment does not alter H2O2 production. NZM neutrophils were stimulated for 1 hour with PMA in the presence of inhibitors as indicated. The PMA-stimulated sample was arbitrarily set at 100% H2O2 production. DPI, NADPH oxidase inhibitor. (E) Cl-amidine treatment does not alter T cell activation. T cells were purified from NZM spleens and stimulated with anti-CD3/CD28 (black bars) in the presence or absence of Cl-amidine. CD25 expression was negligible (white bars) without stimulation. (F) Cl-amidine treatment does not alter lymphocyte proliferation. CFSE-labeled T or B cells were purified from NZM spleens and stimulated with anti-CD3/CD28 or LPS, respectively. After 48–72 hours, in the presence or absence of Cl-amidine, proliferating cells were quantified as described in Methods. For all experiments, data are shown as mean ± SEM, and at least 3 independent experiments are represented. *P < 0.05; ***P < 0.001.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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