Penedo María Aránzazu, Cañeque-Rufo Héctor, Gramage Esther, Herradón Gonzalo
Department of Health and Pharmaceutical Sciences, School of Pharmacy, Universidad San Pablo-CEU, CEU Universities, Madrid, Spain.
Red de Investigación en Atención Primaria de Adicciones, Instituto de Salud Carlos III, MICINN and FEDER, Madrid, Spain.
Front Genet. 2025 Aug 22;16:1634202. doi: 10.3389/fgene.2025.1634202. eCollection 2025.
Microglial cells are key mediators of ethanol-induced neuroinflammation through the release of proinflammatory cytokines and activation of Toll-like receptors. Recently, the signaling pathway initiated by the interaction of the neurotrophic factors pleiotrophin (PTN) and midkine (MK) with receptor-type protein tyrosine phosphatase β/ζ (RPTPβ/ζ) has emerged as a pharmacological target in ethanol-induced neuroinflammatory and neurodegenerative processes. However, the underlying molecular mechanisms remain unclear. In this study, we developed a human co-culture system composed of differentiated SH-SY5Y neuronal cells and HMC3 microglial cells to simulate microglial-neuronal interactions during ethanol exposure. In HMC3 cells, mRNA expression levels were significantly upregulated by ethanol exposure, whereas levels were not altered. In contrast, ethanol exposure caused a significant downregulation of expression in co-cultures. In general, ethanol increased the expression of inflammatory genes in monocultures of HMC3 cells but not in SH-SY5Y cells. In addition, ethanol exposure caused a highly significant upregulation of and in HMC3 cells, which was absent in co-cultures. We also observed a significant attenuation of ethanol-induced increases of inflammatory markers such as and co-cultures, indicating the regulatory role of neuronal-microglial interactions. In conclusion, our study provides novel insights into the modulatory actions of microglial-neuronal interactions in ethanol-induced neuroimmune responses and suggests the therapeutic potential of the PTN/RPTPβ/ζ signaling pathway to prevent the deleterious effects of alcohol on the brain.
小胶质细胞是乙醇诱导神经炎症的关键介质，通过释放促炎细胞因子和激活Toll样受体发挥作用。最近，神经营养因子多效蛋白（PTN）和中期因子（MK）与受体型蛋白酪氨酸磷酸酶β/ζ（RPTPβ/ζ）相互作用引发的信号通路，已成为乙醇诱导的神经炎症和神经退行性变过程中的一个药理学靶点。然而，其潜在的分子机制仍不清楚。在本研究中，我们建立了一个由分化的SH-SY5Y神经元细胞和HMC3小胶质细胞组成的共培养系统，以模拟乙醇暴露期间小胶质细胞与神经元的相互作用。在HMC3细胞中，乙醇暴露显著上调了mRNA表达水平，而水平未改变。相比之下，乙醇暴露导致共培养物中表达显著下调。一般来说，乙醇增加了HMC3细胞单培养物中炎症基因的表达，但在SH-SY5Y细胞中未增加。此外，乙醇暴露导致HMC3细胞中 和 高度显著上调，而在共培养物中则不存在这种情况。我们还观察到乙醇诱导的炎症标志物如 和 在共培养物中的增加显著减弱，表明神经元-小胶质细胞相互作用的调节作用。总之，我们的研究为小胶质细胞-神经元相互作用在乙醇诱导的神经免疫反应中的调节作用提供了新的见解，并提示PTN/RPTPβ/ζ信号通路在预防酒精对大脑的有害影响方面的治疗潜力。
