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<p>Communication between group 3 innate lymphoid cells (ILC3) and other immune cells, as well as intestinal epithelial cells, is pivotal in regulating intestinal inflammation. This study, for the first time, underscores the importance of crosstalk between intestinal endothelial cells (ECs) and ILC3. Our single-cell transcriptome analysis combined with protein expression detection revealed that ECs significantly increased the population of interleukin (IL)-22<sup>+</sup> ILC3 through interactions mediated by endothelin-1 (ET-1) and its receptor endothelin A receptor (EDNRA). Genetic deficiency of EDNRA reduces the proportion of NKp46<sup>+</sup> ILC3 and impairs IL-22 production in a T-cell-independent, cell-intrinsic manner, leading to increased intestinal inflammation. Mechanistically, the ET-1–EDNRA axis modulates hypoxia-inducible factor 1 alpha (HIF-1α) through protein kinase B (AKT) signaling, supporting metabolic adaptation toward glycolysis and providing protection against colitis. Moreover, restoring HIF-1α expression or providing exogenous lactate can alleviate colitis associated with EDNRA deficiency and ILC3 glycolytic dysfunction. These findings underscore the importance of communication between intestinal ECs and ILC3 via the ET-1–EDNRA axis in metabolic adaptation processes within ILC3 and maintaining intestinal homeostasis.</p>

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Endothelial cell–ILC3 crosstalk via the ET-1/EDNRA axis promotes NKp46+ILC3 glycolysis to alleviate intestinal inflammation

  • 期刊论文

  • 发表日期：

    2025年9月10日

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  • Xinyao Li,
  • Yimin Chen,
  • Junyu He,
  • Jian Tang,
  • Chunling Chen,
  • Liyun Meng,
  • Yizhuang Lu,
  • Xiaoming Lyu,
  • Yuxiong Guo,
  • Yumei He

摘要

Communication between group 3 innate lymphoid cells (ILC3) and other immune cells, as well as intestinal epithelial cells, is pivotal in regulating intestinal inflammation. This study, for the first time, underscores the importance of crosstalk between intestinal endothelial cells (ECs) and ILC3. Our single-cell transcriptome analysis combined with protein expression detection revealed that ECs significantly increased the population of interleukin (IL)-22+ ILC3 through interactions mediated by endothelin-1 (ET-1) and its receptor endothelin A receptor (EDNRA). Genetic deficiency of EDNRA reduces the proportion of NKp46+ ILC3 and impairs IL-22 production in a T-cell-independent, cell-intrinsic manner, leading to increased intestinal inflammation. Mechanistically, the ET-1–EDNRA axis modulates hypoxia-inducible factor 1 alpha (HIF-1α) through protein kinase B (AKT) signaling, supporting metabolic adaptation toward glycolysis and providing protection against colitis. Moreover, restoring HIF-1α expression or providing exogenous lactate can alleviate colitis associated with EDNRA deficiency and ILC3 glycolytic dysfunction. These findings underscore the importance of communication between intestinal ECs and ILC3 via the ET-1–EDNRA axis in metabolic adaptation processes within ILC3 and maintaining intestinal homeostasis.