ORIGINAL RESEARCH article
Front. Cell. Neurosci.
Sec. Non-Neuronal Cells
This article is part of the Research TopicCellular and Animal Models of Neurodegenerative and Neuroinflammatory ConditionsView all 4 articles
Galectin-3 shapes microglial phenotype through endogenous and exogenous mechanisms
Provisionally accepted
Lluís Camprubí-Ferrer1*
Yiyi Yang1
Rosalía Fernández-Calle1Antonio Boza-Serrano1,2,3
Juan García-Revilla1,2,3
Javier Frontiñan-Rubio4
Tomas Deierborg1- 1Lund University, Lund, Sweden
- 2Universidad de Sevilla, Seville, Spain
- 3Instituto de Biomedicina de Sevilla, Seville, Spain
- 4Universidad de Castilla-La Mancha, Ciudad Real, Spain
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Galectin-3 (Gal3) is a multifunctional lectin expressed and released by microglia, where it influences diverse processes in both homeostasis and disease. To dissect its intracellular and extracellular roles, we generated Gal3-deficient BV2 microglial cells and systematically assessed how genetic deletion and exogenously added recombinant Gal3 shape microglial physiology. Gal3 deletion increased cell area, mitochondrial activity, and motility without affecting proliferation, linking endogenous Gal3 to microglial energetic control and dynamic cellular physiology. Endogenous Gal3 was required to maintain CD11b surface levels, and restrains TREM2 and Clec7a expression, whereas exogenous Gal3 promoted CD45 internalization and drove a paracrine TNFα release. Endogenous and exogenous Gal3 are synergistically needed for Syk phosphorylation and NOX2 expression. Internalization assays demonstrated that endogenous Gal3 constrained phagocytosis and endocytosis, while exogenous Gal3 enhanced endocytosis in a paracrine manner. In the Alzheimer's disease 5xFAD mouse model, where Gal3 deletion was reported to lower amyloid plaque burden, the absence of Gal3 does not affect microgliosis but elevates Clec7a levels around plaques. Together, these findings reveal Gal3 as a critical regulator of microglial homeostasis, uptake pathways, receptor expression, and inflammatory signalling. We have defined a novel microglial regulation based on endogenous and exogenous pools of Gal3. By identifying a novel Gal3-Clec7a interaction, this work highlights Gal3 as a key modulator of microglial phenotype and a potential target for therapeutic modulation of neuroinflammation.
Keywords: CLEC7A, Endocytosis, galectin-3, Microglia, Neuroinflammation, Phagocytosis
Received: 21 Oct 2025; Accepted: 05 Dec 2025.
Copyright: © 2025 Camprubí-Ferrer, Yang, Fernández-Calle, Boza-Serrano, García-Revilla, Frontiñan-Rubio and Deierborg. 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: Lluís Camprubí-Ferrer
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