Resolution-Phase Immunometabolic Reprogramming by Gelidiopsis variabilis Polysaccharides: Macrophage Polarization and In Vivo Anti-Inflammatory Efficacy

Sulfated polysaccharides from red seaweeds are emerging as versatile bioactive macromolecules. Here, we report that funoran-type galactans from Gelidiopsis variabilis (GV) function as immunometabolic reprogrammers, orchestrating inflammation resolution through targeted remodeling of amino acid and fatty acid metabolism in macrophages, potentially via receptor-mediated pathways. Cold and hot water extraction yielded structurally distinct fractions (360–3006 kDa) characterized by NMR as sulfated galactans with κ-carrageenan motifs and variable sulfation (6.6–21.5%). In RAW264.7 macrophages, fractions GV-1A and GV-2A induced an anti-inflammatory metabolic state characterized by arginine accumulation (from 4.61% to 7.06% of the total amino acid pool), reduced ornithine levels, and complete the elimination of pro-inflammatory myristate (14:0), while upregulating phagocytosis (149% of control). In a carrageenan-induced paw edema model, GV-1A and GV-2A dose-dependently upregulated pro-resolution markers (IL-10, IL-4, TGF-β1, Arg1, HO-1), outperforming the standard drug meloxicam. While the in vitro arginine accumulation suggests functional arginase inhibition, the in vivo Arg1 upregulation reflects a transcriptional response in a complex tissue environment. We propose that these findings collectively support a ‘resolution-phase metabolic phenotype’, a working model whereby GV polysaccharides reprogram macrophage metabolism toward inflammation resolution through context-dependent mechanisms. These findings establish G. variabilis polysaccharides as metabolically active immunomodulators that promote inflammation resolution, with the potential for applications in inflammatory diseases and as a pharmaceutical platform for drug development.