Division of Inflammation Research, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan.
Department of Medicine, Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.
Nat Rev Nephrol. 2019 Aug;15(8):501-520. doi: 10.1038/s41581-019-0158-z.
Inflammasomes are multiprotein innate immune complexes that regulate caspase-dependent inflammation and cell death. Pattern recognition receptors, such as nucleotide-binding oligomerization domain (NOD)-like receptors and absent in melanoma 2 (AIM2)-like receptors, sense danger signals or cellular events to activate canonical inflammasomes, resulting in caspase 1 activation, pyroptosis and the secretion of IL-1β and IL-18. Non-canonical inflammasomes can be activated by intracellular lipopolysaccharides, toxins and some cell signalling pathways. These inflammasomes regulate the activation of alternative caspases (caspase 4, caspase 5, caspase 11 and caspase 8) that lead to pyroptosis, apoptosis and the regulation of other cellular pathways. Many inflammasome-related genes and proteins have been implicated in animal models of kidney disease. In particular, the NLRP3 (NOD-, LRR- and pyrin domain-containing 3) inflammasome has been shown to contribute to a wide range of acute and chronic microbial and non-microbial kidney diseases via canonical and non-canonical mechanisms that regulate inflammation, pyroptosis, apoptosis and fibrosis. In patients with chronic kidney disease, immunomodulation therapies targeting IL-1β such as canakinumab have been shown to prevent cardiovascular events. Moreover, findings in experimental models of kidney disease suggest that small-molecule inhibitors targeting NLRP3 and other inflammasome components are promising therapeutic agents.
炎症小体是一种多蛋白先天免疫复合物，可调节半胱氨酸天冬氨酸蛋白酶（caspase）依赖性炎症和细胞死亡。模式识别受体，如核苷酸结合寡聚化结构域（NOD）样受体和黑色素瘤 2（AIM2）样受体，可感知危险信号或细胞事件以激活经典炎症小体，导致半胱氨酸天冬氨酸蛋白酶 1（caspase 1）激活、细胞焦亡和白细胞介素 1β（IL-1β）和白细胞介素 18（IL-18）的分泌。非经典炎症小体可被细胞内脂多糖、毒素和一些细胞信号通路激活。这些炎症小体调节替代半胱氨酸天冬氨酸蛋白酶（caspase 4、caspase 5、caspase 11 和 caspase 8）的激活，导致细胞焦亡、细胞凋亡和其他细胞通路的调节。许多炎症小体相关基因和蛋白已被牵连到动物肾脏疾病模型中。特别是，NLRP3（NOD、LRR 和 pyrin 结构域包含 3）炎症小体已被证明通过调节炎症、细胞焦亡、细胞凋亡和纤维化的经典和非经典机制，导致广泛的急性和慢性微生物和非微生物肾脏疾病。在慢性肾脏病患者中，针对白细胞介素 1β（如卡那单抗）的免疫调节疗法已被证明可预防心血管事件。此外，肾脏疾病实验模型中的发现表明，针对 NLRP3 和其他炎症小体成分的小分子抑制剂是有前途的治疗药物。
