Institute of Molecular Cell Biology, Jena University Hospital, D-07745 Jena, Germany.
Department of Neonatology, Heidelberg University Children's Hospital, D-69120 Heidelberg, Germany.
Int J Mol Sci. 2021 Mar 4;22(5):2578. doi: 10.3390/ijms22052578.
Microglia, the innate immune cells of the CNS, exhibit long-term response changes indicative of innate immune memory (IIM). Our previous studies revealed IIM patterns of microglia with opposing immune phenotypes: trained immunity after a low dose and immune tolerance after a high dose challenge with pathogen-associated molecular patterns (PAMP). Compelling evidence shows that innate immune cells adopt features of IIM via immunometabolic control. However, immunometabolic reprogramming involved in the regulation of IIM in microglia has not been fully addressed. Here, we evaluated the impact of dose-dependent microglial priming with ultra-low (ULP, 1 fg/mL) and high (HP, 100 ng/mL) lipopolysaccharide (LPS) doses on immunometabolic rewiring. Furthermore, we addressed the role of PI3Kγ on immunometabolic control using naïve primary microglia derived from newborn wild-type mice, PI3Kγ-deficient mice and mice carrying a targeted mutation causing loss of lipid kinase activity. We found that ULP-induced IIM triggered an enhancement of oxygen consumption and ATP production. In contrast, HP was followed by suppressed oxygen consumption and glycolytic activity indicative of immune tolerance. PI3Kγ inhibited glycolysis due to modulation of cAMP-dependent pathways. However, no impact of specific PI3Kγ signaling on immunometabolic rewiring due to dose-dependent LPS priming was detected. In conclusion, immunometabolic reprogramming of microglia is involved in IIM in a dose-dependent manner via the glycolytic pathway, oxygen consumption and ATP production: ULP (ultra-low-dose priming) increases it, while HP reduces it.
小胶质细胞是中枢神经系统的固有免疫细胞，表现出长期的反应变化，表明固有免疫记忆（IIM）。我们之前的研究揭示了小胶质细胞具有相反免疫表型的 IIM 模式：低剂量刺激后产生训练免疫，高剂量刺激后产生免疫耐受。有令人信服的证据表明，固有免疫细胞通过免疫代谢控制来获得 IIM 的特征。然而，小胶质细胞中调节 IIM 的免疫代谢重编程尚未得到充分解决。在这里，我们评估了用超低（ULP，1fg/ml）和高（HP，100ng/ml）浓度脂多糖（LPS）剂量对小胶质细胞进行剂量依赖性预刺激对免疫代谢重编程的影响。此外，我们使用从新生野生型小鼠、PI3Kγ 缺陷型小鼠和携带脂质激酶活性缺失的靶向突变的小鼠中分离得到的幼稚原代小胶质细胞，研究了 PI3Kγ 在免疫代谢控制中的作用。我们发现，ULP 诱导的 IIM 触发了耗氧量和 ATP 产生的增强。相比之下，HP 后则表现出耗氧量和糖酵解活性的抑制，表明存在免疫耐受。PI3Kγ 通过调节 cAMP 依赖性途径抑制糖酵解。然而，由于 LPS 剂量依赖性预刺激，特异性 PI3Kγ 信号对免疫代谢重编程没有影响。总之，小胶质细胞的免疫代谢重编程通过糖酵解途径、耗氧量和 ATP 产生参与 IIM 的发生，其中 ULP（超低剂量预刺激）增加了 IIM，而 HP 则降低了 IIM。
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