Acetylated histones contribute to the immunostimulatory potential of neutrophil extracellular traps in systemic lupus erythematosus
Acetylated histones contribute to the immunostimulatory potential of neutrophil extracellular traps in systemic lupus erythematosus
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DOI：
10.1111/cei.12359
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发表时间：
2015-01-01
影响因子：
4.6
通讯作者：
van der Vlag, J.
中科院分区：
文献类型：
--
作者：
Pieterse, E.;Hofstra, J.;van der Vlag, J.
除了细胞凋亡紊乱和凋亡细胞清除不足外，最近有证据表明中性粒细胞在系统性红斑狼疮（SLE）的病因学中发挥作用。中性粒细胞对各种刺激作出反应时，可以迅速释放修饰有瓜氨酸化组蛋白和抗菌肽的DNA纤维。这些结构被称为中性粒细胞胞外陷阱（NETs）。除了凋亡细胞衍生的微粒之外，这些NET可能包含能够驱动SLE中的自身免疫应答的自身抗原的进一步来源。我们的研究小组最近确定了发生在细胞凋亡过程中的特定组蛋白修饰，在SLE的自身免疫反应中发挥重要作用。在目前的研究中，我们评估了这些先前确定的组蛋白修饰在NET中的存在和免疫刺激潜力。与来自健康供体的NET相比，存在于由SLE衍生的中性粒细胞形成的NET中的组蛋白含有增加量的乙酰化和甲基化残基，我们先前观察到其与细胞凋亡和SLE相关。在诱导NETosis之前，用组蛋白去乙酰化酶（HDAC）抑制剂曲古抑菌素A（TSA）处理中性粒细胞，诱导含有高乙酰化组蛋白的NET，赋予激活巨噬细胞的能力增加。这意味着特定的组蛋白修饰，特别是乙酰化，可能会增强NET在SLE中的免疫刺激潜力。
In addition to disturbed apoptosis and insufficient clearance of apoptotic cells, there is recent evidence for a role of neutrophils in the aetiopathogenesis of systemic lupus erythematosus (SLE). In response to various stimuli, neutrophils can rapidly release DNA fibres decorated with citrullinated histones and anti-microbial peptides. These structures are referred to as neutrophil extracellular traps (NETs). In addition to apoptotic cell-derived microparticles, these NETs may comprise a further source of autoantigens, able to drive the autoimmune response in SLE. Our group recently identified specific histone modifications occurring during apoptosis that play an important role in the autoimmune response in SLE. In the current study, we evaluated the presence and immunostimulatory potential of these previously identified histone modifications in NETs. Compared to NETs from healthy donors, the histones present in NETs formed by SLE-derived neutrophils contain increased amounts of acetylated and methylated residues, which we previously observed to be associated with apoptosis and SLE. Treatment of neutrophils with histone deacetylase (HDAC) inhibitor Trichostatin A (TSA), prior to induction of NETosis, induced NETs containing hyperacetylated histones, endowed with an increased capacity to activate macrophages. This implies that specific histone modifications, in particular acetylation, might enhance the immunostimulatory potential of NETs in SLE.