{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,8,22]],"date-time":"2025-08-22T15:10:10Z","timestamp":1755875410119,"version":"3.44.0"},"reference-count":45,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,8,22]],"date-time":"2025-08-22T00:00:00Z","timestamp":1755820800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:p>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 \u03b2\/\u03b6 (RPTP\u03b2\/\u03b6) 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, <jats:italic>PTN<\/jats:italic> mRNA expression levels were significantly upregulated by ethanol exposure, whereas <jats:italic>MK<\/jats:italic> levels were not altered. In contrast, ethanol exposure caused a significant downregulation of <jats:italic>MK<\/jats:italic> 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 <jats:italic>TLR3<\/jats:italic> and <jats:italic>TLR4<\/jats:italic> in HMC3 cells, which was absent in co-cultures. We also observed a significant attenuation of ethanol-induced increases of inflammatory markers such as <jats:italic>IL-1\u03b2<\/jats:italic> and <jats:italic>CCL2 in<\/jats:italic> 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\/RPTP\u03b2\/\u03b6 signaling pathway to prevent the deleterious effects of alcohol on the brain.<\/jats:p>","DOI":"10.3389\/fgene.2025.1634202","type":"journal-article","created":{"date-parts":[[2025,8,22]],"date-time":"2025-08-22T14:32:42Z","timestamp":1755873162000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Ethanol-induced changes in neurotrophic and immune genes are regulated by receptor-type protein tyrosine phosphatase \u03b2\/\u03b6 (RPTP\u03b2\/\u03b6) and microglial-neuronal interactions"],"prefix":"10.3389","volume":"16","author":[{"given":"Mar\u00eda Ar\u00e1nzazu","family":"Penedo","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"H\u00e9ctor","family":"Ca\u00f1eque-Rufo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Esther","family":"Gramage","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gonzalo","family":"Herrad\u00f3n","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,8,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1186\/s12974-019-1628-8","article-title":"Midbrain microglia mediate a specific immunosuppressive response under inflammatory conditions","volume":"16","author":"Abellanas","year":"2019","journal-title":"J. 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