A Critical Reappraisal of Neutrophil Extracellular Traps and NETosis Mimics Based on Differential Requirements for Protein Citrullination.
A Critical Reappraisal of Neutrophil Extracellular Traps and NETosis Mimics Based on Differential Requirements for Protein Citrullination.
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DOI：
10.3389/fimmu.2016.00461
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发表时间：
2016
影响因子：
7.3
通讯作者：
Andrade F
中科院分区：
文献类型：
--
作者：
Konig MF;Andrade F
NETsis是中性粒细胞死亡的一种抗菌形式，被认为是类风湿关节炎(RA)中瓜氨酸自身抗原和系统性红斑狼疮(SLE)中免疫原性DNA的主要来源。瓜氨酸氨基精氨酸4型脱亚胺酶(PAD4)的激活被认为是中性粒细胞胞外TRAP(Net)形成和NET代谢的关键。因此，PAD4被认为是一种有希望的治疗靶点，可以抑制这两种疾病中Net的形成。在这篇综述中，我们检查了NETsis期间PAD4激活的证据，并提供了实验数据，表明蛋白质瓜氨酸化并不是NETs的普遍特征。我们描述了两个不同的生物学过程，白细胞毒性高瓜氨酸化(LTH)和有丝分裂缺陷，这两个过程被错误地归类为“网织红细胞增多症”。虽然这些模拟蚊虫的形态与蚊虫有相似之处(即细胞外DNA释放)，但它们在生物学上是不同的。因此，这些过程可以很容易地根据它们的刺激、不同生化途径的激活、高瓜氨酸化的存在和抗菌效应功能来分类。NETsis是一种抗微生物形式的细胞死亡，它依赖于NADPH氧化酶，与高瓜氨酸血症无关。相反，LTH不依赖NADPH氧化酶，也不杀菌。相反，LTH代表了一种实现免疫逃避的细菌策略。它是由毛孔形成途径和等效信号触发的，这些信号累积在钙依赖的PADS过度激活、蛋白质过度瓜氨酸化和中性粒细胞死亡。类风湿关节炎中瓜氨酸自身抗原的产生可能是由LTH驱动的，而不是由NETsis驱动的。线粒体DNA(MtDNA)排出是有丝分裂的结构性缺陷的结果，代表着第二个NETase模拟。在干扰素-α和免疫复合体的存在下，这个过程可以产生高度干扰性的氧化线粒体DNA，这在以前被误认为是系统性红斑狼疮的网织红细胞增多症。区分网织红细胞增多症与LTH和有丝分裂缺陷对于了解中性粒细胞损伤在免疫中的作用和人类疾病的发病机制是至关重要的。这为设计人类疾病中这些不同生物过程的特定抑制剂提供了一个框架。
NETosis, an antimicrobial form of neutrophil cell death, is considered a primary source of citrullinated autoantigens in rheumatoid arthritis (RA) and immunogenic DNA in systemic lupus erythematosus (SLE). Activation of the citrullinating enzyme peptidylarginine deiminase type 4 (PAD4) is believed to be essential for neutrophil extracellular trap (NET) formation and NETosis. PAD4 is therefore viewed as a promising therapeutic target to inhibit the formation of NETs in both diseases. In this review, we examine the evidence for PAD4 activation during NETosis and provide experimental data to suggest that protein citrullination is not a universal feature of NETs. We delineate two distinct biological processes, leukotoxic hypercitrullination (LTH) and defective mitophagy, which have been erroneously classified as “NETosis.” While these NETosis mimics share morphological similarities with NETosis (i.e., extracellular DNA release), they are biologically distinct. As such, these processes can be readily classified by their stimuli, activation of distinct biochemical pathways, the presence of hypercitrullination, and antimicrobial effector function. NETosis is an antimicrobial form of cell death that is NADPH oxidase-dependent and not associated with hypercitrullination. In contrast, LTH is NADPH oxidase-independent and not bactericidal. Rather, LTH represents a bacterial strategy to achieve immune evasion. It is triggered by pore-forming pathways and equivalent signals that cumulate in calcium-dependent hyperactivation of PADs, protein hypercitrullination, and neutrophil death. The generation of citrullinated autoantigens in RA is likely driven by LTH, but not NETosis. Mitochondrial DNA (mtDNA) expulsion, the result of a constitutive defect in mitophagy, represents a second NETosis mimic. In the presence of interferon-α and immune complexes, this process can generate highly interferogenic oxidized mtDNA, which has previously been mistaken for NETosis in SLE. Distinguishing NETosis from LTH and defective mitophagy is paramount to understanding the role of neutrophil damage in immunity and the pathogenesis of human diseases. This provides a framework to design specific inhibitors of these distinct biological processes in human disease.
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苏氨酸154在p40phox中的磷酸化是激活中性粒细胞NADPH氧化酶的重要生理信号。
影响因子：
20.3
作者：
Chessa TA;Anderson KE;Hu Y;Xu Q;Rausch O;Stephens LR;Hawkins PT
通讯作者：
Hawkins PT
DOI：
10.1084/jem.20151876
发表时间：
2016-05-02
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Caielli S;Athale S;Domic B;Murat E;Chandra M;Banchereau R;Baisch J;Phelps K;Clayton S;Gong M;Wright T;Punaro M;Palucka K;Guiducci C;Banchereau J;Pascual V
通讯作者：
Pascual V
DOI：
10.1083/jcb.147.3.683
发表时间：
1999-11-01
期刊：
The Journal of cell biology
影响因子：
--
作者：
Blocker A;Gounon P;Larquet E;Niebuhr K;Cabiaux V;Parsot C;Sansonetti P
通讯作者：
Sansonetti P
影响因子：
3.4
作者：
Bentley, CC;Hakansson, A;Wessels, MR
通讯作者：
Wessels, MR
影响因子：
4.9
作者：
Blachère NE;Parveen S;Fak J;Frank MO;Orange DE
通讯作者：
Orange DE