Neuroinflammation is a common pathogenic mechanism for a number of neurodegenerative disorders including Alzheimer's and Parkinson's diseases. Microglia, the immune cells of the brain, contribute to the onset and progression of the neuroinflammation observed in these diseases. Microglia become activated and initiate an inflammatory response by interacting with a diverse set of molecules, including the group of endogenous proteins released upon cell damage, termed damage-associated molecular patterns (DAMPs). One of these molecules, mitochondrial transcription factor A (TFAM), has been shown to induce pro-inflammatory and cytotoxic responses of microglia in vitro. Here, we demonstrate that TFAM injected into the cisterna magna of male Sprague-Dawley rats upregulates (i) the expression of monocyte chemotactic protein (MCP)-1, interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α and nuclear factor-kappa B inhibitor alpha (NF-κBIA) in the hippocampus; (ii) the expression of MCP-1, IL-1β and TNF-α in the frontal cortex; and (iii) IL-1β protein concentration in both these brain regions. These same inflammatory mediators are upregulated in isolated rat microglia following their in vitro exposure to extracellular TFAM. Blocking the receptor for advanced glycation endproducts (RAGE) and the macrophage antigen complex (Mac)-1 by specific antibodies inhibited the TFAM-induced secretion of MCP-1 by THP-1 monocytic cells, which were used to model human microglia. Our data support the hypothesis that extracellular TFAM can interact with RAGE and Mac-1 to function as a DAMP that causes pro-inflammatory microglial activation. Blocking this interaction may represent a potential target for attenuating the neuroinflammation observed in neurodegenerative diseases.

中文翻译：

---

模式识别受体介导细胞外线粒体转录因子A（TFAM）的促炎作用。

神经炎症是许多神经退行性疾病的常见致病机制，包括阿尔茨海默氏病和帕金森氏病。小胶质细胞是大脑的免疫细胞，有助于在这些疾病中观察到的神经炎症的发生和发展。小胶质细胞通过与多种分子相互作用而被激活并引发炎症反应，这些分子包括细胞损伤后释放的内源性蛋白质，称为损伤相关分子模式（DAMPs）。这些分子之一，线粒体转录因子A（TFAM），已显示出在体外诱导小胶质细胞的促炎和细胞毒性反应。在这里，我们证明了将TFAM注入雄性Sprague-Dawley大鼠的大水罐中会上调（i）单核细胞趋化蛋白（MCP）-1的表达，海马中的白介素（IL）-1β，IL-6，肿瘤坏死因子（TNF）-α和核因子-κB抑制剂α（NF-κBIA）；（ii）MCP-1，IL-1β和TNF-α在额叶皮层的表达；（iii）在这两个大脑区域中的IL-1β蛋白浓度。这些相同的炎性介质在体外暴露于细胞外TFAM后在分离的大鼠小胶质细胞中上调。通过特异抗体阻断晚期糖基化终产物（RAGE）和巨噬细胞抗原复合物（Mac）-1的受体，可抑制TFAM诱导的THP-1单核细胞分泌MCP-1，MCP-1被用来模拟人小胶质细胞。我们的数据支持以下假设，即细胞外TFAM可以与RAGE和Mac-1相互作用以充当引起促炎性小胶质细胞活化的DAMP。