程序性细胞坏死在疾病中的研究进展

Necroptosis Related Diseases

细胞坏死自从被发现具有严格的"程序性调控"特征以来,其信号转导机制以及相关疾病机理引起了学术界广泛关注并展开大量研究。程序性细胞坏死(necroptosis)是一种不同于凋亡及传统坏死的新的细胞死亡方式,主要由肿瘤坏死因子受体(tumor necrosis factor receptor, TNFR)家族或Toll样受体(Toll-like receptor, TLR)家族调控启动。死亡受体被激活之后,与受体蛋白相互作用的两个蛋白激酶RIP1(receptor interacting protein kinase 1)和RIP3被激活,进而招募RIP3的底物MLKL(mixed lineage kinase domain-like protein)并催化它发生磷酸化,磷酸化的MLKL发生寡聚化转位到质膜上,引起膜通透性的改变,最终实现坏死的发生。细胞坏死是一种促炎性的程序性细胞死亡方式,其过程中伴有大量细胞内容物的释放。如损伤相关的模式分子(damage associated molecular patterns, DAMP)的释放,会激活机体的免疫应答,因此其广泛参与到各种疾病的病理生理过程中,包括神经退行性疾病、感染性炎症性疾病、缺血再灌注损伤、肿瘤发生及转移等。细胞坏死抑制剂有望被应用于对这些疾病的干预来改善患者病情及预后。该文将详细阐述程序性细胞坏死在胚胎发育、组织稳态、炎症相关疾病、肿瘤、神经系统相关疾病等疾病中的作用,并对其在临床治疗中的应用进行回顾及展望。

Necroptosis is a new mode of cell death that different from apoptosis and traditional necrosis,it is mainly induced by ligation of tumor necrosis factor receptor(TNFR) family or Toll-like receptor(TLR) family. Once the death receptors are activated, RIP1 and RIP3 would be activated, and then RIP3 recruits and phosphorylates its substrate MLKL. The phosphorylated MLKL releases its auto-inhibition and forms oligomers, which translocate to the membrane compartments, cause membrane leakage. Unlike apoptosis, necroptosis is a form of pro-inflammatory cell death, which releases a large amount of cellular contents, such as DAMP(damage associated molecular patterns), thus necroptosis involves in lots of pathophysiological processes of diseases including neurodegenerative diseases, infectious inflammatory diseases, ischemia-reperfusion injury, tumorigenesis, etc. Necroptosis inhibitors are expected to be used in these diseases to help with improving the patient’s conditions. This review elaborates on the role of necroptosis in embryonic development, tissue homeostasis, inflammatory diseases, tumors, neurological diseases and other diseases, aiming to provide prospects for the diagnosis and treatment of necroptosis-related diseases.