Galectin-1 induces macrophage immunometabolic reprogramming, modulates T cell immunity and attenuates atherosclerotic plaque formation

Abstract

Background and aimsAtherosclerosis 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. MethodsEffects 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 cultures experiments were performed to study T cell differentiation, macrophage function, polarization end energy metabolism. The impact of Gal-1 on human macrophages was further evaluated in endarterectomy specimens. ResultsGal-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. ConclusionGal-1 protects against atherosclerosis associated with reprogramming macrophages and tuning T cell immunity through glycan-dependent and -independent pathways.