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<p>Group 3 innate lymphoid cells (ILC3) are crucial in neonatal necrotizing enterocolitis (NEC); however, the underlying mechanisms remain elusive. Here, we identify NKp46⁻CCR6⁻ (double-negative, DN) ILC3s as the dominant pathogenic subset driving NEC via IL-17 A secretion, which disrupts intestinal barrier integrity. Mechanistically, Atg5 activates autophagy in DN ILC3s during NEC. Atg5 conditional knockout in RORγt⁺ cells mitigates NEC, reduces DN ILC3 accumulation and IL-17 A production. Atg5 deficiency also decreases HIF-1α chromatin accessibility and transcriptional activity, shifting DN ILC3 metabolism from glycolysis to fatty acid oxidation. Lipidomics reveals phosphatidylcholine as a key downstream metabolite of Atg5-mediated autophagy. Phosphatidylcholine supplementation suppresses DN ILC3-driven inflammation, restores metabolic homeostasis, elevates <i>Clostridium</i> abundance, and ameliorates NEC in mice. Importantly, human NEC tissues exhibit increased ILC3 proportions, autophagic activity, and IL-17 A/IL-22 secretion. Thus, we uncover an Atg5–autophagy–glycolipid metabolic axis in DN ILC3s that drives NEC pathogenesis, providing a promising therapeutic target for neonatal NEC.</p>

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Blockade of NKp46⁻ CCR6⁻ ILC3 autophagy protects against necrotizing enterocolitis by restoring energy metabolism balance in mice

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月19日

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  • Junyu He,
  • Meiqi Chen,
  • Laiqin Peng,
  • Qiqiong Wang,
  • Yizhuang Lu,
  • Yimin Chen,
  • Xinyao Li,
  • Yanling Mou,
  • Jianjun Wang,
  • Yuxiong Guo,
  • Kai Wu,
  • Yumei He

摘要

Group 3 innate lymphoid cells (ILC3) are crucial in neonatal necrotizing enterocolitis (NEC); however, the underlying mechanisms remain elusive. Here, we identify NKp46⁻CCR6⁻ (double-negative, DN) ILC3s as the dominant pathogenic subset driving NEC via IL-17 A secretion, which disrupts intestinal barrier integrity. Mechanistically, Atg5 activates autophagy in DN ILC3s during NEC. Atg5 conditional knockout in RORγt⁺ cells mitigates NEC, reduces DN ILC3 accumulation and IL-17 A production. Atg5 deficiency also decreases HIF-1α chromatin accessibility and transcriptional activity, shifting DN ILC3 metabolism from glycolysis to fatty acid oxidation. Lipidomics reveals phosphatidylcholine as a key downstream metabolite of Atg5-mediated autophagy. Phosphatidylcholine supplementation suppresses DN ILC3-driven inflammation, restores metabolic homeostasis, elevates Clostridium abundance, and ameliorates NEC in mice. Importantly, human NEC tissues exhibit increased ILC3 proportions, autophagic activity, and IL-17 A/IL-22 secretion. Thus, we uncover an Atg5–autophagy–glycolipid metabolic axis in DN ILC3s that drives NEC pathogenesis, providing a promising therapeutic target for neonatal NEC.