Birkle Timothy J Y, Brown Guy C
Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.
Front Aging Neurosci. 2023 Mar 15;15:1120952. doi: 10.3389/fnagi.2023.1120952. eCollection 2023.
Microglia are brain macrophages and play beneficial and/or detrimental roles in many brain pathologies because of their inflammatory and phagocytic activity. Microglial inflammation and phagocytosis are thought to be regulated by spleen tyrosine kinase (Syk), which is activated by multiple microglial receptors, including TREM2 (Triggering Receptor Expressed on Myeloid Cells 2), implicated in neurodegeneration. Here, we have tested whether Syk inhibitors can prevent microglia-dependent neurodegeneration induced by lipopolysaccharide (LPS) in primary neuron-glia cultures. We found that the Syk inhibitors BAY61-3606 and P505-15 (at 1 and 10 μM, respectively) completely prevented the neuronal loss induced by LPS, which was microglia-dependent. Syk inhibition also prevented the spontaneous loss of neurons from older neuron-glia cultures. In the absence of LPS, Syk inhibition depleted microglia from the cultures and induced some microglial death. However, in the presence of LPS, Syk inhibition had relatively little effect on microglial density (reduced by 0-30%) and opposing effects on the release of two pro-inflammatory cytokines (IL-6 decreased by about 45%, TNFα increased by 80%). Syk inhibition also had no effect on the morphological transition of microglia exposed to LPS. On the other hand, inhibition of Syk reduced microglial phagocytosis of beads, synapses and neurons. Thus, Syk inhibition in this model is most likely neuroprotective by reducing microglial phagocytosis, however, the reduced microglial density and IL-6 release may also contribute. This work adds to increasing evidence that Syk is a key regulator of the microglial contribution to neurodegenerative disease and suggests that Syk inhibitors may be used to prevent excessive microglial phagocytosis of synapses and neurons.
小胶质细胞是脑内巨噬细胞，因其炎症和吞噬活性，在许多脑部病理过程中发挥有益和/或有害作用。小胶质细胞的炎症和吞噬作用被认为受脾酪氨酸激酶（Syk）调节，Syk可被多种小胶质细胞受体激活，包括与神经退行性变有关的髓样细胞表达的触发受体2（TREM2）。在此，我们测试了Syk抑制剂是否能预防原代神经元-胶质细胞培养物中脂多糖（LPS）诱导的小胶质细胞依赖性神经退行性变。我们发现，Syk抑制剂BAY61-3606和P505-15（分别为1μM和10μM）完全预防了LPS诱导的神经元丢失，这是小胶质细胞依赖性的。Syk抑制还预防了较老的神经元-胶质细胞培养物中神经元的自发丢失。在无LPS的情况下，Syk抑制使培养物中的小胶质细胞耗竭并诱导了一些小胶质细胞死亡。然而，在有LPS的情况下，Syk抑制对小胶质细胞密度的影响相对较小（降低0 - 30%），并且对两种促炎细胞因子的释放产生相反的影响（IL-6降低约45%，TNFα增加80%）。Syk抑制对暴露于LPS的小胶质细胞的形态转变也没有影响。另一方面，抑制Syk可减少小胶质细胞对珠子、突触和神经元的吞噬作用。因此，在该模型中，Syk抑制最有可能通过减少小胶质细胞吞噬作用而具有神经保护作用，然而，小胶质细胞密度的降低和IL-6释放的减少也可能起作用。这项工作进一步证明了Syk是小胶质细胞对神经退行性疾病作用的关键调节因子，并表明Syk抑制剂可用于预防小胶质细胞对突触和神经元的过度吞噬。
