Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina-IPN, Apartado Postal 11340, Plan de San Luis y Díaz Mirón s/n, Casco de Santo Tomás, Ciudad de México, México.
Laboratorio de Hepatología Experimental, Departamento de Farmacología, Cinvestav-IPN, Apartado Postal 14-740, Ciudad de México, México.
Biochem Pharmacol. 2023 Nov;217:115861. doi: 10.1016/j.bcp.2023.115861. Epub 2023 Oct 18.
The NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome pathway is mainly responsible for the activation and release of a cascade of proinflammatory mediators that contribute to the development of hepatic diseases. During alcoholic liver disease development, the NLRP3 inflammasome pathway contributes to the maturation of caspase-1, interleukin (IL)-1β, and IL-18, which induce a robust inflammatory response, leading to fibrosis by inducing profibrogenic hepatic stellate cell (HSC) activation. Substantial evidence demonstrates that nonalcoholic fatty liver disease (NAFLD) progresses to nonalcoholic steatohepatitis (NASH) via NLRP3 inflammasome activation, ultimately leading to fibrosis and hepatocellular carcinoma (HCC). Activation of the NLRP3 inflammasome in NASH can be attributed to several factors, such as reactive oxygen species (ROS), gut dysbiosis, leaky gut, which allow triggers such as cardiolipin, cholesterol crystals, endoplasmic reticulum stress, and uric acid to reach the liver. Because inflammation triggers HSC activation, the NLRP3 inflammasome pathway performs a central function in fibrogenesis regardless of the etiology. Chronic hepatic activation of the NLRP3 inflammasome can ultimately lead to HCC; however, inflammation also plays a role in decreasing tumor growth. Some data indicate that NLRP3 inflammasome activation plays an important role in autoimmune hepatitis, but the evidence is scarce. Most researchers have reported that NLRP3 inflammasome activation is essential in liver injury induced by a variety of drugs and hepatotropic virus infection; however, few reports indicate that this pathway can play a beneficial role by inducing liver regeneration. Modulation of the NLRP3 inflammasome appears to be a suitable strategy to treat liver diseases.
NOD 样受体家族含 pyrin 结构域蛋白 3（NLRP3）炎症小体途径主要负责激活和释放一系列促炎介质，这些介质有助于肝脏疾病的发展。在酒精性肝病发展过程中，NLRP3 炎症小体途径有助于半胱氨酸蛋白酶-1（caspase-1）、白细胞介素（IL）-1β和 IL-18 的成熟，这些物质诱导强烈的炎症反应，通过诱导纤维生成性肝星状细胞（HSC）激活导致纤维化。大量证据表明，非酒精性脂肪性肝病（NAFLD）通过 NLRP3 炎症小体激活进展为非酒精性脂肪性肝炎（NASH），最终导致纤维化和肝细胞癌（HCC）。NASH 中 NLRP3 炎症小体的激活可归因于几种因素，如活性氧（ROS）、肠道菌群失调、肠道渗漏，这些因素允许如心磷脂、胆固醇晶体、内质网应激和尿酸等触发物到达肝脏。由于炎症触发 HSC 激活，NLRP3 炎症小体途径在纤维化中发挥核心作用，无论病因如何。NLRP3 炎症小体在慢性肝激活最终可导致 HCC；然而，炎症也在降低肿瘤生长中发挥作用。一些数据表明，NLRP3 炎症小体激活在自身免疫性肝炎中起重要作用，但证据不足。大多数研究人员报告称，NLRP3 炎症小体激活在各种药物和嗜肝病毒感染引起的肝损伤中是必不可少的；然而，很少有报道表明该途径可以通过诱导肝再生发挥有益作用。NLRP3 炎症小体的调节似乎是治疗肝脏疾病的一种合适策略。
