法国国家科学研究中心Romeo Ricci，Zhirong Zhang和意大利那不勒斯费德里科二世大学Maria Antonietta De Matteis共同合作，近期取得重要工作进展。他们研究发现核内体成分的改变促进NLRP3炎症小体的活化。相关研究成果2022年11月28日在线发表于《自然—免疫学》杂志上。
据介绍，炎症复合物在先天免疫反应中起关键作用。含有蛋白3的NLR家族pyrin结构域（NLRP3）炎症小体在多种细胞应激下被激活。然而，NLRP3受体启动炎症小体组装的传感机制目前仍不明确。
研究人员发现，NLRP3炎症小体激活剂主要集中于内质网-内体膜接触位点（EECS）的破坏上。这种缺陷导致磷脂酰肌醇4磷酸（PI4P）在核内体的积累，并导致内体对转高尔基体网络运输（ETT）的损害，这是NLRP3核内体的募集和随后炎症小体激活的必要步骤。降低核内体PI4P水平可防止NLRP3的核内体关联并抑制炎症小体激活。EECS或ETT的破坏足以增强核内体PI4P水平，将NLRP3招募到核内体，并增强NLRP3炎症小体的激活。骨髓区ETT缺陷的小鼠更易受脂多糖诱导的败血症的影响。
因此，这一研究确定了导致核内体NLRP3募集和炎症小体激活的独特细胞机制。
附：英文原文
Title: Distinct changes in endosomal composition promote NLRP3 inflammasome activation
Author: Zhang, Zhirong, Venditti, Rossella, Ran, Li, Liu, Zengzhen, Vivot, Karl, Schrmann, Annette, Bonifacino, Juan S., De Matteis, Maria Antonietta, Ricci, Romeo
Issue&Volume: 2022-11-28
Abstract: Inflammasome complexes are pivotal in the innate immune response. The NLR family pyrin domain containing protein 3 (NLRP3) inflammasome is activated in response to a broad variety of cellular stressors. However, a primary and converging sensing mechanism by the NLRP3 receptor initiating inflammasome assembly remains ill defined. Here, we demonstrate that NLRP3 inflammasome activators primarily converge on disruption of endoplasmic reticulum–endosome membrane contact sites (EECS). This defect causes endosomal accumulation of phosphatidylinositol 4-phosphate (PI4P) and a consequent impairment of endosome-to-trans-Golgi network trafficking (ETT), necessary steps for endosomal recruitment of NLRP3 and subsequent inflammasome activation. Lowering endosomal PI4P levels prevents endosomal association of NLRP3 and inhibits inflammasome activation. Disruption of EECS or ETT is sufficient to enhance endosomal PI4P levels, to recruit NLRP3 to endosomes and to potentiate NLRP3 inflammasome activation. Mice with defects in ETT in the myeloid compartment are more susceptible to lipopolysaccharide-induced sepsis. Our study thus identifies a distinct cellular mechanism leading to endosomal NLRP3 recruitment and inflammasome activation.
DOI: 10.1038/s41590-022-01355-3
Source: https://www.nature.com/articles/s41590-022-01355-3
来源：科学网 小柯机器人