ORIGINAL RESEARCH article
Front. Genet.
Sec. Genetics of Aging
Volume 16 - 2025 | doi: 10.3389/fgene.2025.1634202
This article is part of the Research TopicDecoding Neurodegeneration: Insights into the Pathways of Neurological DeclineView all articles
Ethanol-induced changes in neurotrophic and immune genes are regulated by receptor-type protein tyrosine phosphatase β/ζ (RPTPβ/ζ) and microglial-neuronal interactions
Provisionally accepted
- CEU San Pablo University, Madrid, Spain
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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, PTN mRNA expression levels were significantly upregulated by ethanol exposure, whereas MK levels were not altered. In contrast, ethanol exposure caused a significant downregulation of MK 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 TLR3 and TLR4 in HMC3 cells, which was absent in co-cultures. We also observed a significant attenuation of ethanol-induced increases of inflammatory markers such as IL-1β and CCL2 in cocultures, indicating the regulatory role of neuronal-microglial interactions. In conclusion, our study provides novel insights into the modulatory actions of microglial-neuronal interactions in ethanolinduced neuroimmune responses and suggests the therapeutic potential of the PTN/RPTPβ/ζ signaling pathway to prevent the deleterious effects of alcohol on the brain.
Keywords: alcohol, RPTPβ/ζ, co-culture, Neuroinflammation, pleiotrophin, midkine. 2
Received: 23 May 2025; Accepted: 18 Jul 2025.
Copyright: © 2025 Penedo, Cañeque-Rufo, Gramage and Herradon. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Gonzalo Herradon, CEU San Pablo University, Madrid, Spain
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