简介

坏死性凋亡，又叫程序性坏死，是一种受调控的由RIP1和RIP3激酶介导的坏死性细胞死亡方式。坏死性凋亡的特征包括：细胞质膜完整性会在早期丢失，细胞内容物泄漏，以及细胞器肿胀。通过坏死性凋亡方式死亡的细胞缺乏典型的凋亡特征，例如，细胞膜出泡，染色质固缩和核小体内DNA裂解成180 bp的梯状DNA，但也可能表现出TUNEL阳性。

Necroptosis is a form of regulated necrotic cell death mediated by RIP1 kinase and RIP3. Necroptosis is characterized by early loss of plasma membrane integrity, leakage of intracellular contents, and organelle swelling. The cells dying through necroptosis lack the typical apoptotic characteristics, such as membrane blebbing, chromatin condensation, and intranucleosomal DNA cleavage into 180 bp DNA laddering, but may show TUNEL positivity.

坏死性凋亡一般机制

坏死性凋亡作为一种调节性坏死的细胞死亡形式的建立，颠覆了传统的观念，即坏死只能是压倒性压力造成的被动过程。如表所述，坏死性凋亡可由已知的激活炎症和细胞死亡的细胞外刺激触发。RIP1激酶是该途径关键的上游调节因子，它通过多种磷酸化和泛素化事件来发挥复杂的调控作用，这些事件决定了细胞的生死命运。坏死性凋亡的细胞内信号传导途径涉及复合物IIb或坏死小体的形成，其中RIP1激酶结合并激活RIP3。坏死性凋亡的执行步骤涉及通过磷酸化激活假激酶MLKL，从而导致MLKL易位至质膜和细胞质膜（plasma and cytoplasmic membranes），从而调节离子通道活性导致坏死。

The establishment of necroptosis as a form of regulated necrotic cell death overturned the traditional belief that necrosis could only be a passive process caused by overwhelming stress. Necroptosis can be triggered by extracellular stimuli known to activate inflammation and cell death as summarized in the table. RIP1 kinase, a key upstream regulator of the pathway, is modulated intricately by multiple phosphorylation and ubiquitination events, which dictate the cellular fate to life or death. The intracellular signaling pathway of necroptosis involves the formation of complex IIb or necrosome, wherein RIP1 kinase binds and activates RIP3. The execution step of necroptosis involves the activation of pseudokinase MLKL by phosphorylation, resulting in MLKL translocation to the plasma and cytoplasmic membranes where it modulates ion channel activities to lead to necrosis.

研究坏死性凋亡的意义

在许多涉及细胞死亡和炎症的疾病的小鼠模型中，如在大脑，心脏，视网膜和肾脏的急性缺血再灌注损伤中，已经证明，抑制坏死性凋亡可以减轻小鼠的病理状态。创伤性脑损伤；年龄相关性黄斑变性；动脉粥样硬化炎症性肠病；高雪氏病；和同种异体排斥反应。抑制坏死性凋亡可能为治疗多种涉及炎症和细胞死亡的人类疾病提供益处。

Inhibition of necroptosis has been shown to mitigate pathology in mouse models of numerous diseases involving cell death and inflammation, such as acute ischemiareperfusion injury in the brain, heart, retina, and kidney; traumatic brain injury; age-related macular degeneration; atherosclerosis; inflammatory bowel disease; Gaucher’s disease; and allograft rejection. Inhibition of necroptosis might provide benefits to the treatment of multiple human diseases involving inflammation and cell death.

更多坏死性凋亡机制

最常用的坏死性凋亡抑制剂非Necrostatin-1莫属了。研究坏死性凋亡，OMG，选它！