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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 5

PAD inhibition reduces MPO and immune complex deposition in the kidneys of NZM mice.

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PAD inhibition reduces MPO and immune complex deposition in the kidneys ...
(A) Urine albumin/creatinine ratios were determined for the 2 groups of NZM mice presented in Figure 4. (B) 3-micron sections were prepared from formalin-fixed kidneys of 26-week-old mice, and activity index was calculated as described in Methods. (C) Glomerular MPO deposition was determined as described in Methods and in Supplemental Figure 2. Discrete areas of MPO staining were counted, with at least 10 glomeruli considered per mouse. (D) Glomeruli were also stained for IgG and C3 deposition. At least 10 glomeruli were scored for staining intensity on a scale of 0 to 3+, with average intensity then calculated for each kidney. *P < 0.05. One P value that approaches significance is presented as a number. Box-and-whisker plots represent 10 mice per group, with boxes representing the median, 25th percentile, and 75th percentile, while whiskers delineate the minimum and maximum values. (E–H) Representative glomeruli from the vehicle group (E and G) and the Cl-amidine group (F and H). IgG is stained red and C3 is stained green. Original magnification, ×400. Scale bar: 25 microns.

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

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