Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan.
Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Mol Neurobiol. 2019 Feb;56(2):1167-1187. doi: 10.1007/s12035-018-1135-4. Epub 2018 Jun 6.
Microglial activation has long been recognized as a hallmark of neuroinflammation. Recently, the bacillus Calmette-Guerin (BCG) vaccine has been reported to exert neuroprotective effects against several neurodegenerative disorders. Trehalose-6,6'-dibehenate (TDB) is a synthetic analogue of trehalose-6,6'-dimycolate (TDM, also known as the mycobacterial cord factor) and is a new adjuvant of tuberculosis subunit vaccine currently in clinical trials. Both TDM and TDB can activate macrophages and dendritic cells through binding to C-type lectin receptor Mincle; however, its action mechanism in microglia and their relationship with neuroinflammation are still unknown. In this article, we found that TDB inhibited LPS-induced M1 microglial polarization in primary microglia and BV-2 cells. However, TDB itself had no effects on IKK, p38, and JNK activities or cytokine expression. In contrast, TDB activated ERK1/2 through PLC-γ1/PKC signaling and in turn decreased LPS-induced NF-κB nuclear translocation. Furthermore, TDB-induced AMPK activation via PLC-γ1/calcium/CaMKKβ-dependent pathway and thereby enhanced M2 gene expressions. Interestingly, knocking out Mincle did not alter the anti-inflammatory and M2 polarization effects of TDB in microglia. Conditional media from LPS-stimulated microglial cells can induce in vitro neurotoxicity, and this action was attenuated by TDB. Using a mouse neuroinflammation model, we found that TDB suppressed LPS-induced M1 microglial activation and sickness behavior, but promoted M2 microglial polarization in both WT and Mincle mice. Taken together, our results suggest that TDB can act independently of Mincle to inhibit LPS-induced inflammatory response through PLC-γ1/PKC/ERK signaling and promote microglial polarization towards M2 phenotype via PLC-γ1/calcium/CaMKKβ/AMPK pathway. Thus, TDB may be a promising therapeutic agent for the treatment of neuroinflammatory diseases.
小胶质细胞的激活一直被认为是神经炎症的标志。最近，卡介苗（BCG）疫苗被报道对几种神经退行性疾病具有神经保护作用。海藻糖-6,6'-二油酰基（TDB）是海藻糖-6,6'-二酰基（TDM，也称为分枝杆菌cord 因子）的合成类似物，是目前正在临床试验中的结核亚单位疫苗的新型佐剂。TDM 和 TDB 均可通过与 C 型凝集素受体 Mincle 结合来激活巨噬细胞和树突状细胞；然而，其在小胶质细胞中的作用机制及其与神经炎症的关系尚不清楚。在本文中，我们发现 TDB 抑制了 LPS 诱导的原代小胶质细胞和 BV-2 细胞中 M1 小胶质细胞极化。然而，TDB 本身对 IKK、p38 和 JNK 活性或细胞因子表达没有影响。相反，TDB 通过 PLC-γ1/PKC 信号激活 ERK1/2，进而减少 LPS 诱导的 NF-κB 核转位。此外，TDB 通过 PLC-γ1/钙/CaMKKβ依赖性途径诱导 AMPK 激活，从而增强 M2 基因表达。有趣的是，敲除 Mincle 并没有改变 TDB 在小胶质细胞中的抗炎和 M2 极化作用。LPS 刺激的小胶质细胞的条件培养基可在体外诱导神经毒性，而 TDB 可减弱该作用。使用小鼠神经炎症模型，我们发现 TDB 抑制了 LPS 诱导的 M1 小胶质细胞激活和疾病行为，但在 WT 和 Mincle 小鼠中均促进了 M2 小胶质细胞极化。综上所述，我们的结果表明，TDB 可以独立于 Mincle 发挥作用，通过 PLC-γ1/PKC/ERK 信号抑制 LPS 诱导的炎症反应，并通过 PLC-γ1/钙/CaMKKβ/AMPK 途径促进小胶质细胞向 M2 表型极化。因此，TDB 可能是治疗神经炎症性疾病的一种有前途的治疗剂。
