Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC 3168, Australia.
Department of Molecular and Translational Science, Monash University, Clayton, VIC 3168, Australia.
Biomolecules. 2021 Apr 28;11(5):646. doi: 10.3390/biom11050646.
Chronic inflammatory disorders are characterised by aberrant and exaggerated inflammatory immune cell responses. Modes of extrinsic cell death, apoptosis and necroptosis, have now been shown to be potent drivers of deleterious inflammation, and mutations in core repressors of these pathways underlie many autoinflammatory disorders. The receptor-interacting protein (RIP) kinases, RIPK1 and RIPK3, are integral players in extrinsic cell death signalling by regulating the production of pro-inflammatory cytokines, such as tumour necrosis factor (TNF), and coordinating the activation of the NOD-like receptor protein 3 (NLRP3) inflammasome, which underpin pathological inflammation in numerous chronic inflammatory disorders. In this review, we firstly give an overview of the inflammatory cell death pathways regulated by RIPK1 and RIPK3. We then discuss how dysregulated signalling along these pathways can contribute to chronic inflammatory disorders of the joints, skin, and gastrointestinal tract, and discuss the emerging evidence for targeting these RIP kinases in the clinic.
慢性炎症性疾病的特征是异常和过度的炎症免疫细胞反应。现在已经表明，细胞外死亡方式（细胞凋亡和坏死性凋亡）是导致有害炎症的有力驱动因素，而这些途径的核心抑制剂的突变是许多自身炎症性疾病的基础。受体相互作用蛋白 (RIP) 激酶 RIPK1 和 RIPK3 通过调节促炎细胞因子（如肿瘤坏死因子 (TNF)）的产生以及协调 NOD 样受体蛋白 3 (NLRP3) 炎症小体的激活，是细胞外死亡信号的重要参与者，后者是许多慢性炎症性疾病中病理性炎症的基础。在这篇综述中，我们首先概述了 RIPK1 和 RIPK3 调节的炎症细胞死亡途径。然后，我们讨论了这些途径中失调的信号如何导致关节、皮肤和胃肠道的慢性炎症性疾病，并讨论了针对这些 RIP 激酶在临床上的新兴证据。
