Gal-1 treatment reduces early atherosclerosis independently of circulating IL-10 signaling.

Gal-1 reprograms human and mouse macrophages in the plaque towards an anti-inflammatory phenotype.

Anti-inflammatory effects of Gal-1 are partially independent of its glycan-binding ability.

Gal-1 modulates T cell immunity by increasing Tregs and IL-10-producing T cells and by promoting a regulatory Th17 response.

Atherosclerosis is a chronic immunometabolic disease driven by lipid accumulation and immune cell infiltration. Macrophages and T cells play key roles throughout plaque development. Galectin-1 (Gal-1), a glycan-binding protein, modulates immune functions in these cells and has been reported to attenuate atherosclerosis, though its mechanisms remain incompletely understood. Here, we investigated the effects of Gal-1 on macrophages and T cells during plaque formation.

Effects of Gal-1 on atherosclerosis, macrophages and T cells during lesion formation were studied in Apoe−/− mice treated with recombinant Gal-1. Complementary mouse peritoneal foam cell and in vitro macrophage and T cell culture experiments were performed to study T cell differentiation, macrophage function, polarization and energy metabolism. The impact of Gal-1 on human macrophages was further evaluated in endarterectomy specimens.

Gal-1 treatment reduced lesion size and increased circulating IL-10 levels, inversely correlating with plaque burden. Unexpectedly, IL-10 neutralization also mitigated atherosclerosis, indicating that its action is at least partially IL-10–independent. In plaques, Gal-1 promoted anti-inflammatory macrophage phenotypes, mirrored by a quiescent metabolic and anti-inflammatory profile in foamy macrophages ex vivo. The use of the Gal-1E71Q variant revealed that these effects were only partly dependent on glycan binding. Beyond IL-10, Gal-1 reshaped cytokine profiles by increasing IL-17, IL-22, and IL-23, consistent with a macrophage-driven regulatory Th17 response, alongside higher frequencies of IL-10–producing and regulatory T cells.

Gal-1 protects against atherosclerosis associated with reprogramming macrophages and tuning T cell immunity through glycan-dependent and -independent pathways.

Cytokine

Treg

Macrophage polarization

OXPHOS

Glycolysis

Foam cell

Glycan

© 2025 The Authors. Published by Elsevier B.V.