Division of Rheumatology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109-5680, USA.
J Clin Invest. 2013 Jul;123(7):2981-93. doi: 10.1172/JCI67390. Epub 2013 Jun 3.
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.
最近的证据表明，中性粒细胞胞外诱捕网（NET）的形成增强激活了浆细胞样树突状细胞，并作为 SLE 中自身抗原的来源。我们提出，异常的 NET 形成也与器官损伤以及人类 SLE 特征性的过早血管疾病有关。在这里，我们证明了新西兰混合 2328（NZM）狼疮小鼠模型中 NET 形成的增强。NZM 小鼠还产生了针对 NET 的自身抗体以及人 cathelicidin/LL37（CRAMP）的同源物，后者在 NET 中被外化。用 Cl-amidine（一种肽基精氨酸脱亚氨酶（PAD）抑制剂）治疗 NZM 小鼠以阻断 NET 形成，并评估狼疮样疾病活动、内皮功能和促血栓形成表型。Cl-amidine 治疗抑制了 NZM 体内 NET 的形成，并显著改变了循环自身抗体谱和补体水平，同时减少了肾小球 IgG 沉积。此外，Cl-amidine 增加了骨髓内皮祖细胞的分化能力，改善了内皮依赖性血管舒张功能，并显著延迟了光化学损伤诱导的动脉血栓形成时间。总的来说，这些发现表明 PAD 抑制可以调节对狼疮发病机制和疾病活动至关重要的表型，并且可能是减轻狼疮患者心血管风险的重要策略。
