Peptidylarginine deiminases 2 and 4 modulate innate and adaptive immune responses in TLR-7 dependent lupus
Peptidylarginine deiminases 2 and 4 modulate innate and adaptive immune responses in TLR-7 dependent lupus
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DOI：
10.1172/jci.insight.124729
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发表时间：
2018-12-06
期刊：
影响因子：
8
通讯作者：
Kaplan, Mariana J.
中科院分区：
文献类型：
--
作者：
Liu, Yudong;Lightfoot, Yaima L.;Kaplan, Mariana J.
多肽精氨酸脱亚胺酶PAD2和PAD4参与多种自身免疫性疾病的发病。PAD4在系统性红斑狼疮(SLE)中的致病作用可能是通过其在促进自身抗原外化、免疫失调和器官损伤的中性粒细胞外细胞外陷阱(Net)的形成而起作用。这种酶在小鼠自身免疫模型中的作用尚不清楚，因为PAN-PAD化学抑制剂改善了临床表型，而PAD4-K0模型给出了相互矛盾的结果。PAD2在系统性红斑狼疮中的作用尚未被研究。研究PAD2和PAN在TLR-7依赖的狼疮自身免疫中的不同作用。PADI4(-/-)表现出自身抗体、I型干扰素反应、免疫细胞激活、血管功能障碍和净免疫原性降低。PADI2(-/-)小鼠表现出Th亚群极化的消除，某些疾病表现与WT相比有所减轻，但程度低于PADI4(-/-)小鼠。RNA测序分析表明，PAD-KO淋巴器官中的免疫相关通路有明显的调制。人类T细胞同时表达PADS和PAD4，当暴露于PAD2或PAD4抑制剂时，表现出Th1极化的消除。这些结果表明，靶向PAD2和/或PAD4活性通过天然免疫和获得性免疫的不同作用来调节狼疮中失调的TLR-7依赖的免疫反应。靶向PADS的化合物可能在T细胞介导的疾病中具有潜在的治疗作用。
The peptidylarginine deiminases PAD2 and PAD4 are implicated in the pathogenesis of several autoimmune diseases. PAD4 may be pathogenic in systemic lupus erythematosus (SLE) through its role in neutrophil extracellular trap (NET) formation that promotes autoantigen externalization, immune dysregulation, and organ damage. The role of this enzyme in mouse models of autoimmunity remains unclear, as pan-PAD chemical inhibitors improve clinical phenotype, whereas PAD4-K0 models have given conflicting results. The role of PAD2 in SLE has not been investigated. The differential roles of PAD2 and PAN in TLR-7-dependent lupus autoimmunity were examined. Padi4(-/-) displayed decreased autoantibodies, type I IFN responses, immune cell activation, vascular dysfunction, and NET immunogenicity. Padi2(-/-) mice showed abrogation of Th subset polarization, with some disease manifestations reduced compared with WT but to a lesser extent than Padi4(-/-) mice. RNA sequencing analysis revealed distinct modulation of immune-related pathways in PAD-KO lymphoid organs. Human T cells express both PADs and, when exposed to either PAD2 or PAD4 inhibitors, displayed abrogation of Th1 polarization. These results suggest that targeting PAD2 and/or PAD4 activity modulates dysregulated TLR-7-dependent immune responses in lupus through differential effects of innate and adaptive immunity. Compounds that target PADs may have potential therapeutic roles in T cell-mediated diseases.