Targeting macrophage glycogen metabolism attenuates ulcerative colitis by suppressing IL-1β production through UDPG-P2Y14 signaling

Ulcerative colitis (UC) is a chronic inflammatory disease of the colon characterized by recurrent episodes of mucosal inflammation. During disease progression, macrophages are recruited into the intestinal lamina propria and polarized toward a pro-inflammatory phenotype, where they exacerbate tissue injury by secreting cytokines such as IL-1β, IL-6, and TNF-α. Among these, IL-1β plays a central role, exhibiting both immunomodulatory and pro-inflammatory functions that correlate with disease severity. This study revealed that glycogen metabolism critically regulates IL-1β production and secretion in inflammatory macrophages. Mechanistically, uridine diphosphate-glucose (UDPG), a metabolic intermediate of glycogen metabolism, activates the P2Y₁₄ receptor, leading to the downstream upregulation of STAT1 expression and enhanced IL-1β production. In parallel, activation of the UDPG-P2Y₁₄ axis suppresses intracellular cAMP levels, thereby facilitating inflammasome activation and caspase-1 cleavage, ultimately driving IL-1β secretion. Importantly, the glycogen phosphorylase inhibitor ameliorates dextran sulfate sodium induced UC in mice by inhibiting glycogen metabolism. These findings highlight the UDPG-P2Y₁₄ pathway as a potential therapeutic target for IL-1β-driven inflammatory diseases.