Immunoregulatory effects of necroptosis in bacterial infections.
Immunoregulatory effects of necroptosis in bacterial infections.
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DOI：
10.1016/j.cyto.2016.09.024
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发表时间：
2016-12
期刊：
影响因子：
3.8
通讯作者：
Dane Parker;A. Prince
中科院分区：
文献类型：
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作者：
Dane Parker;A. Prince
坏死性凋亡是一种越来越受到重视的细胞死亡调节途径，其在细菌感染的发病机制中的作用不同于凋亡或焦亡。它已被证明在某些感染和缺血性损伤模型中具有病理后果[1]，但在特定类型的细菌感染中可能是有益的[2]。坏死性凋亡细胞死亡的标志是坏死体激酶、受体相互作用蛋白激酶1（RIPK 1）和3（RIPK 3）以及混合谱系激酶样（MLKL）蛋白的参与[1，3，4]。RIPK 1的磷酸化导致RIPK 3的募集和活化，募集至质膜，MLKL寡聚化，随后是膜透化[1，4]。与其他细胞死亡途径一样，激活坏死性凋亡的激酶受到高度调节，并与在细胞凋亡中起作用的半胱天冬酶的表达相关[3]。坏死性凋亡发生在缺乏胱天蛋白酶-8的情况下，胱天蛋白酶-8通过切割RIPK 1和RIPK 3来平衡坏死性凋亡。胱天蛋白酶-8还靶向脱乌蛋白酶CYLD，阻止RIPK 1引发坏死性凋亡[3，5]。坏死性凋亡通常由TNFR信号传导激活，但也可由多种机制诱导，包括：细胞死亡受体、毒素、toll样受体、DNA和RNA传感器以及干扰素[3]。坏死性凋亡通过细胞内内容物的释放、细胞死亡期间的损伤相关分子模式（DAMPS）触发炎症。炎症是宿主反应的一个重要方面，是控制感染所必需的。然而，炎症的调节是至关重要的，因为与过度炎症相关的局部病理学限制病原体清除并导致炎性疾病的发展。我们观察到这种平衡对于确定不同部位金黄色葡萄球菌感染的结果是重要的。金黄色葡萄球菌引发通常与肺部病理学相关的强烈的中性粒细胞主导的炎症反应。肺泡巨噬细胞的调节作用在平衡促炎和抗炎信号传导中是重要的。我们的初步研究表明S.金黄色葡萄球菌激活巨噬细胞中的坏死性凋亡[6]。坏死性凋亡细胞死亡依赖于毒素诱导的孔形成，与α-毒素、酚可溶性调节蛋白和杀白细胞素AB有关，但不依赖于PVL。通过使用化学抑制剂（necrostatin-1 s，RIPK 1的抑制剂）或使用基因缺失小鼠（RIP 3）干扰坏死性凋亡，导致调节促炎信号的肺泡巨噬细胞存活增加。来自Ripk 3 −/−小鼠的肺泡巨噬细胞表达的主要抗炎受体CD 206和CD 200 R水平升高[6]。Ripk 3 −/−小鼠具有显著的
Necroptosis is an increasingly appreciated pathway of regulated cell death, which has a role in the pathogenesis of bacterial infection distinct from that of apoptosis or pyroptosis. It has been shown to have pathological consequences in some models of infection and ischemic injury [1], but can be beneficial in specific types of bacterial infection [2]. The hallmark of necroptotic cell death is the involvement of the necrosome kinases, receptor interacting protein kinases 1 (RIPK1) and 3 (RIPK3) and the mixed lineage kinase like (MLKL) protein [1, 3, 4]. Phosphorylation of RIPK1 leads to recruitment and activation of RIPK3, recruitment to the plasma membrane, MLKL oligomerization, followed by membrane permeabilization [1, 4]. Like the other cell death pathways the kinases that activate necroptosis are highly regulated and linked to the expression of the caspases that function in apoptosis [3]. Necroptosis occurs in the absence of caspase-8 that acts to counter-balance necroptosis by cleaving RIPK1 and RIPK3. Caspase-8 also targets the deubquitinase CYLD preventing RIPK1 initiation of necroptosis [3, 5]. Necroptosis is classically activated by TNFR signaling but can also be induced by a variety of mechanisms including: cell death receptors, toxins, toll-like receptors, DNA and RNA sensors and interferons [3]. Necroptosis triggers inflammation through the release of intracellular contents, damage associated molecular patterns (DAMPS) during cell death. Inflammation is an important aspect of the host response and is required for control of infection. However, regulation of inflammation is critical as the local pathology associated with excessive inflammation limits pathogen clearance and leads to the development of inflammatory diseases. It is this balance that we observe to be important in determining outcomes at different sites of infection with Staphylococcus aureus.In the airway S. aureus trigger a robust neutrophil dominated inflammatory response often associated with lung pathology. The regulatory effects of alveolar macrophages are important in balancing pro and anti-inflammatory signaling. Our initial studies demonstrated that S. aureus activates necroptosis in macrophages [6]. The necroptotic cell death was dependent upon toxin-induced pore formation associated with; α-toxin, phenol soluble modulins and leukocidin AB, but not PVL. Interfering with necroptosis, either through the use of chemical inhibitors (necrostatin-1s, an inhibitor of RIPK1) or using gene deleted mice (RIP3), resulted in increased survival of alveolar macrophages that regulate proinflammatory signaling. Alveolar macrophages from Ripk3−/− mice expressed increased levels of CD206 and CD200R, major anti-inflammatory receptors [6]. Ripk3−/− mice had significantly