NLRP3 Inflammasome Priming and Activation Are Regulated by a Phosphatidylinositol-Dependent Mechanism.
NLRP3 Inflammasome Priming and Activation Are Regulated by a Phosphatidylinositol-Dependent Mechanism.
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DOI：
10.4049/immunohorizons.2200058
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发表时间：
2022-08-29
期刊：
影响因子：
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通讯作者：
Anand PK
中科院分区：
文献类型：
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作者：
Hamilton C;Olona A;Leishman S;MacDonald-Ramsahai K;Cockcroft S;Larrouy-Maumus G;Anand PK
脂质稳态失衡与免疫信号差异相关，并与代谢紊乱密切相关。然而，脂质影响免疫信号传导的多种方式仍然不明确。磷脂酰肌醇 (PI) 与许多免疫疾病有关，主要由其磷酸化状态决定。相比之下，连接到 PI 上的两条脂肪酸链的重要性仍然未知。在这项研究中，通过使用基于质谱的检测，我们证明了 PI 酰基链在调节小鼠巨噬细胞中 NOD 样受体家族包含热蛋白结构域 3 (NLRP3) 炎症小体的启动和激活步骤中的作用。响应 NLRP3 刺激，缺乏 ABC 转运蛋白 ATP 结合盒亚家族 B 成员 1 (ABCB1)（流出脂质衍生物）的细胞显示出有缺陷的炎性体激活。从机制上讲，Abcb1 缺陷改变了总 PI 构型，表现出短链与长链 PI 酰基脂质的比例降低。因此，Abcb1 缺陷引发了含有 Toll/IL-1R 结构域的接头蛋白（结合 PI-二磷酸盐的 TLR 接头蛋白）的快速降解，导致 TLR 依赖性信号传导缺陷，从而导致 NLRP3 表达。此外，这还伴随着 NLRP3 Ser291 位点磷酸化的增加，并导致炎症小体激活减弱。向野生型细胞中外源补充亚油酸 (LA)，而不是花生四烯酸，可重新配置 PI 酰基链。因此，补充 LA 会增加含有 Toll/IL-1R 结构域的接头蛋白降解、升高 NLRP3 磷酸化并消除炎症小体激活。此外，NLRP3 Ser291 磷酸化依赖于 PGE2 诱导的蛋白激酶 A 信号传导，因为在富含 LA 的细胞中对该途径的药理抑制会使 NLRP3 去磷酸化。总而言之，据我们所知，我们的研究揭示了一种有助于校准免疫反应的新型代谢炎症回路。免疫地平线，2022 年，6：642–659。
Imbalance in lipid homeostasis is associated with discrepancies in immune signaling and is tightly linked to metabolic disorders. The diverse ways in which lipids impact immune signaling, 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. In this study, by using a mass spectrometry–based assay, we demonstrate a role for PI acyl group chains in regulating both the priming and activation steps of the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome in mouse macrophages. In response to NLRP3 stimuli, cells deficient in ABC transporter ATP Binding Cassette Subfamily B Member 1 (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 initiated the rapid degradation of Toll/IL-1R domain–containing adaptor protein, the TLR adaptor protein that binds PI -bisphosphate, resulting in defective TLR-dependent signaling, and thus NLRP3 expression. Moreover, this accompanied increased NLRP3 phosphorylation at the Ser291 position and contributed to blunted inflammasome activation. Exogenously supplementing wild-type cells with linoleic acid (LA), but not arachidonic acid, reconfigured PI acyl chains. Accordingly, LA supplementation increased Toll/IL-1R domain–containing adaptor protein degradation, elevated NLRP3 phosphorylation, and abrogated inflammasome activation. Furthermore, NLRP3 Ser291 phosphorylation was dependent on PGE2-induced protein kinase A signaling because pharmacological inhibition of this pathway in LA-enriched cells dephosphorylated NLRP3. Altogether, our study reveals, to our knowledge, a novel metabolic-inflammatory circuit that contributes to calibrating immune responses. ImmunoHorizons, 2022, 6: 642–659.