Ganglioside-mediated macrophage plasticity

Jeongtae Kim

doi:10.7180/kmj.25.128

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Editorial Ganglioside-mediated macrophage plasticity: Jeongtae Kim; Kosin Medical Journal 2025;40(3):157-159.
DOI: https://doi.org/10.7180/kmj.25.128
Published online: September 25, 2025

Department of Anatomy, Jeju National University College of Medicine, Jeju, Korea

Corresponding Author: Jeongtae Kim, DVM, PhD Department of Anatomy, Jeju National University College of Medicine, 102 Jejudaehang-ro, Jeju 63243, Korea Tel: +82-64-754-3856 Fax: +82-64-702-2687 E-mail: kimjt78@kosin.ac.kr

• Received: August 25, 2025 • Revised: September 9, 2025 • Accepted: September 10, 2025

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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See the article "Gangliosides enhance M2-polarized macrophage elongation induced by IL-4 and IL-13" on page 188.

Macrophages are central regulators of the immune system that exhibit remarkable functional plasticity in response to environmental cues [1]. Their ability to polarize into distinct phenotypes—classically activated (M1) macrophages with pro-inflammatory functions and alternatively activated (M2) macrophages associated with tissue repair and immune resolution—has long been a focus of immunological research [2,3]. A consistent hallmark of M2 polarization is macrophage elongation, a morphological shift that correlates with functional changes such as enhanced motility and reduced phagocytosis [4]. Despite this well-documented association, the molecular mechanisms linking macrophage morphology with functional specialization remain insufficiently understood.

This study investigated the functional role of gangliosides, including ganglioside monosialodihexosyl ganglioside (GM3) and ganglioside disialodihexosyl ganglioside (GD3), in shaping macrophage morphology and behavior during M2 polarization induced by interleukin (IL)-4 and IL-13 [5]. Using both the RAW264.7 macrophage cell line and primary bone marrow-derived macrophages, it was demonstrated that IL-4/IL-13 stimulation markedly upregulated ganglioside biosynthetic enzymes, particularly St3gal5 and St8sia1, leading to increased GM3 and GD3 levels. These gangliosides proved essential for macrophage elongation, a defining feature of M2 polarization, as pharmacological inhibition of ganglioside synthesis with D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP) or genetic silencing of St3gal5 abrogated the elongation phenotype. Functionally, elevated ganglioside levels also promoted macrophage migration in response to monocyte chemoattractant protein-1, while simultaneously reducing phagocytic activity, suggesting a shift toward a tissue repair, immune-regulatory phenotype. Remarkably, treatment with GM3 alone was sufficient to mimic the effects of IL-4/IL-13, underscoring its potent role in driving M2-like changes. Mechanistically, the study identified phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) and mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK) signaling pathways as mediators of GM3-induced elongation, whereas pathways such as STAT6 and p38 were non-essential in this setting. These findings establish GM3 and GD3 as key bioactive lipids that regulate macrophage plasticity within the IL-4/IL-13 microenvironment [5].

Gangliosides are glycosphingolipids enriched in cell membranes, particularly within lipid rafts, where they modulate receptor clustering and signal transduction [6]. Although prior studies have implicated gangliosides in processes such as cell differentiation, immune modulation, and tumor biology, their role in macrophage polarization has remained less defined [6-8]. This study directly addressed that gap, showing that IL-4/IL-13–induced M2 polarization increased GM3 and GD3 synthesis, accompanied by pronounced macrophage elongation. Mechanistic evidence reinforced this causal link: inhibition of ganglioside biosynthesis by D-PDMP or siRNA-mediated knockdown of St3gal5, the enzyme responsible for GM3 synthesis, substantially reduced elongation. These interventions not only disrupted morphology but also reversed M2-associated functional changes, such as enhanced migration and suppressed phagocytosis. Taken together, the results identify gangliosides as indispensable mediators of the morphological and functional adaptations characteristic of M2 macrophages.

A major strength of the study lies in demonstrating how morphological elongation translated into functional outcomes. Using transwell migration assays, it was shown that GM3 enhances macrophage motility, thereby facilitating migration in response to chemotactic signals. This has direct relevance for tissue repair, where the effective recruitment of M2 macrophages is critical for wound resolution and fibrosis control. Conversely, ganglioside-mediated elongation was associated with diminished phagocytic capacity, evidenced by decreased uptake of latex beads. This observation is consistent with the established role of M2 macrophages in prioritizing anti-inflammatory and tissue-remodeling functions over pathogen clearance. Notably, St3gal5 knockdown restored phagocytosis, providing clear confirmation that gangliosides directly shape functional trade-offs.

The identification of gangliosides, particularly GM3, as central modulators of M2 macrophage polarization introduces a lipid-centric paradigm in immune cell regulation. From a cell biology perspective, this study illustrates how specific components of the plasma membrane, notably gangliosides, govern cytoskeletal remodeling and morphological transformation through their influence on membrane microdomains and downstream signaling cascades. The activation of PI3K/AKT and MEK/ERK pathways by GM3 is consistent with its role in promoting elongation and motility, processes essential for macrophages involved in tissue remodeling, wound healing, and inflammation resolution [9,10]. From an immunological standpoint, the study provides new insights into how macrophages fine-tune effector functions not only via cytokine stimulation but also through intrinsic membrane lipid composition. This suggests therapeutic potential in targeting ganglioside synthesis or metabolism to modulate macrophage activity in diseases marked by dysregulated immune responses, including chronic inflammation, fibrosis, and cancer. Future directions should include in vivo validation using animal models of inflammatory or fibrotic disease to evaluate the therapeutic consequences of manipulating ganglioside levels. Investigating downstream ganglioside metabolites, such as sialotriaosylceramide and disialoganglioside could reveal broader regulatory networks influencing the macrophage phenotype [11]. Additional studies should also explore how ganglioside-rich lipid rafts coordinate receptor clustering and signaling in macrophages during immune responses, and whether these processes are altered in pathological contexts such as neuroinflammation or tumor progression.

Ultimately, the study reinforces an essential principle: immune cell behavior is governed not only by cytokines and transcription factors but also by the lipid composition of the plasma membrane. Recognizing gangliosides as active participants in immune regulation opens promising new directions for research and therapeutic intervention.

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Conflicts of interest

Jeongtae Kim is an editorial board member of the journal but was not involved in the peer reviewer selection, evaluation, or decision process of this article. No other potential conflicts of interest relevant to this article were reported.

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None.

Author contributions

All the work was done by Jeongtae Kim.

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Ganglioside-mediated macrophage plasticity

Kosin Med J. 2025;40(3):157-159. Published online September 25, 2025

DOI: https://doi.org/10.7180/kmj.25.128

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