NLRP3 inflammasome priming and activation are regulated by a novel phosphatidylinositol-dependent mechanism
NLRP3 inflammasome priming and activation are regulated by a novel phosphatidylinositol-dependent mechanism
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NLRP3 炎症小体启动和激活由一种新型磷脂酰肌醇依赖性机制调节
DOI：
10.1101/2020.01.14.905075
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Hamilton C
中科院分区：
文献类型：
--
作者：
Hamilton C
脂质稳态的失衡与免疫信号的差异有关，并与代谢紊乱密切相关。然而，脂质影响免疫信号的不同方式仍然不明确。磷脂磷脂酰肌醇(PI)与多种免疫疾病有关，主要由其磷酸化状态决定。相比之下，连接在PI上的两条脂肪酸链的意义尚不清楚。在这里，通过基于质谱学的分析，我们展示了PI酰基链在调节小鼠巨噬细胞中NLRP3炎症体的启动和激活步骤中的作用。作为对NLRP3刺激的响应，ABC转运蛋白ABCB1的缺陷细胞显示出有缺陷的炎性小体激活。从机理上讲，ABCB1缺陷改变了总的PI构型，表现出短链和长链PI-酰基脂的比率降低。因此，ABCB1缺乏导致TIRAP的快速降解，TIRAP是与PI(4，5)-磷酸结合的TLR接头蛋白。此外，这伴随着Ser293位NLRP3磷酸化增加和炎性小体钝化激活。外源补充亚油酸，而不是花生四烯酸，重组PI酰链。因此，补充亚油酸增加了TIRAP的降解，增加了NLRP3的磷酸化，并抑制了炎性小体的激活。综上所述，我们的研究揭示了一种新的代谢-炎症回路，有助于校准免疫反应。
Imbalance in lipid homeostasis is associated with discrepancies in immune signalling and is tightly linked to metabolic disorders. The diverse ways in which lipids impact immune signalling, however, remain ambiguous. The phospholipid phosphatidylinositol (PI), which is implicated in numerous immune disorders, is chiefly defined by its phosphorylation status. By contrast, the significance of the two fatty acid chains attached to the PI remains unknown. Here, by employing a mass-spectrometry-based assay, we demonstrate a role for PI acyl group chains in regulating both the priming and activation steps of the NLRP3 inflammasome in mouse macrophages. In response to NLRP3 stimuli, cells deficient in ABC transporter ABCB1, which effluxes lipid derivatives, revealed defective inflammasome activation. Mechanistically,Abcb1-deficiency shifted the total PI configuration exhibiting a reduced ratio of short-chain to long-chain PI-acyl lipids. Consequently,Abcb1-deficiency resulted in rapid degradation of TIRAP, the TLR adaptor protein which binds PI(4,5)-phosphate. Moreover, this accompanied increased NLRP3 phosphorylation at the Ser293 position and blunted inflammasome activation. Exogenously supplementing WT cells with linoleic acid, but not arachidonic acid, reconfigured PI acyl chains. Accordingly, linoleic acid supplementation increased TIRAP degradation, elevated NLRP3 phosphorylation, and abrogated inflammasome activation. Altogether, our study reveals a novel metabolic-inflammatory circuit which contributes to calibrating immune responses.