Metabolic Induction of Trained Immunity through the Mevalonate Pathway
Metabolic Induction of Trained Immunity through the Mevalonate Pathway
复制标题
DOI：
10.1016/j.cell.2017.11.025
复制
发表时间：
2018-01-11
期刊：
影响因子：
64.5
通讯作者：
Netea, Mihai G.
中科院分区：
文献类型：
--
作者：
Bekkering, Siroon;Arts, Rob J. W.;Netea, Mihai G.
先天免疫细胞在感染或接种疫苗期间受到微生物产品的刺激后可以产生长期记忆。在这里，我们报告说，代谢信号可以诱导训练免疫力。药理学和遗传学实验表明，胆固醇合成途径的激活，而不是胆固醇本身的合成，对于骨髓细胞的训练至关重要。相反，代谢物甲羟戊酸是通过激活IGF 1-R和mTOR以及随后的炎症途径中的组蛋白修饰的训练介质。阻断甲羟戊酸生成的他汀类药物可阻止训练性免疫诱导。此外，甲羟戊酸激酶缺陷并积累甲羟戊酸的高免疫球蛋白D综合征（HIDS）患者的单核细胞在免疫学和表观遗传水平上具有组成性训练的免疫表型，这可以解释这些患者经历的无菌炎症的攻击。揭示甲羟戊酸在训练免疫中的作用有助于我们理解HIDS的病理生理学，并为训练免疫过度激活的临床病症确定新的治疗靶点。
Innate immune cells can develop long-term memory after stimulation by microbial products during infections or vaccinations. Here, we report that metabolic signals can induce trained immunity. Pharmacological and genetic experiments reveal that activation of the cholesterol synthesis pathway, but not the synthesis of cholesterol itself, is essential for training of myeloid cells. Rather, the metabolite mevalonate is the mediator of training via activation of IGF1-R and mTOR and subsequent histone modifications in inflammatory pathways. Statins, which block mevalonate generation, prevent trained immunity induction. Furthermore, monocytes of patients with hyper immunoglobulin D syndrome (HIDS), who are mevalonate kinase deficient and accumulate mevalonate, have a constitutive trained immunity phenotype at both immunological and epigenetic levels, which could explain the attacks of sterile inflammation that these patients experience. Unraveling the role of mevalonate in trained immunity contributes to our understanding of the pathophysiology of HIDS and identifies novel therapeutic targets for clinical conditions with excessive activation of trained immunity.