Pieterse E, Hofstra J, Berden J, Herrmann M, Dieker J, van der Vlag J
Department of Nephrology, Radboud University Medical Center, Nijmegen, the Netherlands.
Clin Exp Immunol. 2015 Jan;179(1):68-74. doi: 10.1111/cei.12359.
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.
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）的发病机制中起作用。响应各种刺激，中性粒细胞可迅速释放装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外，这些NETs可能构成自身抗原的另一个来源，能够驱动SLE中的自身免疫反应。我们小组最近发现了细胞凋亡过程中发生的特定组蛋白修饰，这些修饰在SLE的自身免疫反应中起重要作用。在本研究中，我们评估了这些先前鉴定的组蛋白修饰在NETs中的存在及其免疫刺激潜力。与健康供体的NETs相比，由SLE衍生的中性粒细胞形成的NETs中存在的组蛋白含有增加量的乙酰化和甲基化残基，我们之前观察到这些残基与细胞凋亡和SLE相关。在诱导NETosis之前，用组蛋白脱乙酰酶（HDAC）抑制剂曲古抑菌素A（TSA）处理中性粒细胞，可诱导含有高乙酰化组蛋白的NETs，其激活巨噬细胞的能力增强。这意味着特定的组蛋白修饰，特别是乙酰化，可能会增强NETs在SLE中的免疫刺激潜力。
