Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA.
Nat Immunol. 2021 May;22(5):550-559. doi: 10.1038/s41590-021-00886-5. Epub 2021 Mar 11.
The NLRP3 inflammasome is a multimeric cytosolic protein complex that assembles in response to cellular perturbations. This assembly leads to the activation of caspase-1, which promotes maturation and release of the inflammatory cytokines interleukin-1β (IL-1β) and IL-18, as well as inflammatory cell death (pyroptosis). The inflammatory cytokines contribute to the development of systemic low-grade inflammation, and aberrant NLRP3 activation can drive a chronic inflammatory state in the body to modulate the pathogenesis of inflammation-associated diseases. Therefore, targeting NLRP3 or other signaling molecules downstream, such as caspase-1, IL-1β or IL-18, has the potential for great therapeutic benefit. However, NLRP3 inflammasome-mediated inflammatory cytokines play dual roles in mediating human disease. While they are detrimental in the pathogenesis of inflammatory and metabolic diseases, they have a beneficial role in numerous infectious diseases and some cancers. Therefore, fine tuning of NLRP3 inflammasome activity is essential for maintaining proper cellular homeostasis and health. In this Review, we will cover the mechanisms of NLRP3 inflammasome activation and its divergent roles in the pathogenesis of inflammation-associated diseases such as cancer, atherosclerosis, diabetes and obesity, highlighting the therapeutic potential of targeting this pathway.
NLRP3 炎性小体是一种多聚体细胞溶质蛋白复合物，可响应细胞扰动而组装。这种组装导致半胱天冬酶-1 的激活，促进炎性细胞因子白细胞介素-1β (IL-1β) 和白细胞介素-18 的成熟和释放，以及炎性细胞死亡（细胞焦亡）。炎性细胞因子有助于全身低度炎症的发展，异常的 NLRP3 激活可导致体内慢性炎症状态，从而调节炎症相关疾病的发病机制。因此，靶向 NLRP3 或其他下游信号分子，如半胱天冬酶-1、IL-1β 或 IL-18，具有巨大的治疗益处。然而，NLRP3 炎性小体介导的炎性细胞因子在介导人类疾病方面发挥着双重作用。虽然它们在炎症和代谢性疾病的发病机制中是有害的，但它们在许多传染性疾病和一些癌症中具有有益的作用。因此，精细调节 NLRP3 炎性小体的活性对于维持适当的细胞内稳态和健康至关重要。在这篇综述中，我们将介绍 NLRP3 炎性小体激活的机制及其在癌症、动脉粥样硬化、糖尿病和肥胖等炎症相关疾病发病机制中的不同作用，强调了靶向该途径的治疗潜力。
