Department of Biology, University of British Columbia Okanagan Campus, Kelowna, British Columbia, Canada V1V 1V7.
Mediators Inflamm. 2022 Mar 25;2022:9946439. doi: 10.1155/2022/9946439. eCollection 2022.
Alzheimer's disease (AD) is characterized by chronic neuroinflammation, which is partially mediated by dysregulated functions of glial cells. Cardiolipin (CL) is a phospholipid normally confined to the inner mitochondrial membrane; however, it has been detected in human sera, indicating that it can exist in the extracellular space where it may interact with nearby cells. Although CL has been shown to modulate several functions of microglia in a toll-like receptor (TLR) 4-dependent manner, the effects of extracellular CL on astrocytes are unknown. In addition to their homeostatic functions, astrocytes participate in neuroimmune responses of the brain and express TLR 4. Therefore, we hypothesized that extracellular CL (1) modulates the secretion of cytokines and cytotoxins by astrocytes, as well as their phagocytic activity, and (2) acts by interacting with astrocyte TLR 4. We demonstrate that CL inhibits the lipopolysaccharide- (LPS-) induced secretion of cytotoxins and expression of glial fibrillary acidic protein (GFAP) by human U118 MG astrocytic cells. CL alone upregulates the phagocytic activity of human astrocytic cells and primary murine astrocytes. CL in combination with LPS upregulates secretion of interleukin (IL)-1 by astrocytic cells. Furthermore, CL alone increases the secretion of monocyte chemoattractant protein (MCP)-1 by astrocytic cells, which is blocked by the TLR 4-specific antagonist TAK-242. We demonstrate that CL upregulates MCP-1 secretion in the absence of its natural carrier protein, 2-glycoprotein 1, indicating that CL may be bioactive in the brain where this protein is not present. Lastly, we show that CL downregulates the expression of astrocytic TLR 4, implying that CL engages this receptor, as its activation has been shown to lead to its degradation. Overall, our study extends the list of cell type functions of which CL modulates and provides evidence that CL, or liposomes containing this phospholipid can be used to modulate specific neuroimmune functions of astrocytes.
阿尔茨海默病（AD）的特征是慢性神经炎症，部分由神经胶质细胞功能失调介导。心磷脂（CL）是一种通常局限于线粒体内膜的磷脂；然而，它已在人血清中检测到，表明它可以存在于细胞外空间，在那里它可能与附近的细胞相互作用。虽然已经表明 CL 以 Toll 样受体（TLR）4 依赖的方式调节小胶质细胞的几种功能，但细胞外 CL 对星形胶质细胞的影响尚不清楚。除了它们的稳态功能外，星形胶质细胞还参与大脑的神经免疫反应并表达 TLR 4。因此，我们假设细胞外 CL（1）调节星形胶质细胞细胞因子和细胞毒素的分泌以及它们的吞噬活性，（2）通过与星形胶质细胞 TLR 4 相互作用起作用。我们证明 CL 抑制人 U118 MG 星形胶质细胞的脂多糖（LPS）诱导的细胞毒素分泌和神经胶质酸性蛋白（GFAP）的表达。CL 单独上调人星形胶质细胞和原代鼠星形胶质细胞的吞噬活性。CL 与 LPS 联合上调星形胶质细胞分泌白细胞介素（IL）-1。此外，CL 单独增加星形胶质细胞单核细胞趋化蛋白（MCP）-1的分泌，这被 TLR 4 特异性拮抗剂 TAK-242 阻断。我们证明 CL 在没有其天然载体蛋白 2-糖蛋白 1 的情况下上调 MCP-1 分泌，这表明 CL 可能在大脑中具有生物活性，而这种蛋白质不存在。最后，我们表明 CL 下调星形胶质细胞 TLR 4 的表达，这意味着 CL 与该受体结合，因为其激活已被证明导致其降解。总的来说，我们的研究扩展了 CL 调节的细胞类型功能列表，并提供了证据表明 CL 或含有这种磷脂的脂质体可用于调节星形胶质细胞的特定神经免疫功能。
