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<p>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 P2Y<sub>14</sub> receptor, leading to the downstream upregulation of STAT1 expression and enhanced IL-1β production. In parallel, activation of the UDPG–P2Y<sub>14</sub> 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–P2Y<sub>14</sub> pathway as a potential therapeutic target for IL-1β-driven inflammatory diseases.</p> Graphical Abstract <p></p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年2月4日

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  • Shuai Tong,
  • Tao Zhu,
  • Shuqi Liang,
  • Yuxiao Cui,
  • Yuan Ma,
  • Xin Zhang,
  • Yuhan Bian,
  • Keke Wei,
  • Sha Wu,
  • Jingwei Ma

摘要

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.

Graphical Abstract