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

Cellular & Molecular Immunology volume 22, pages 1459–1477 (2025)Cite this article

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Abstract

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.

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Fig. 1: Endothelial cell-derived ET-1 enhances ILC3 functionality by interacting with EDNRA.
Fig. 2: NKp46+ ILC3 orchestrate the pathological alterations observed in mouse colitis induced by ET-1/EDNRA intervention.
Fig. 3: Specific crosstalk between EC-derived ET-1 and EDNRA on ILC3 mediates the protective effect of NKp46+ILC3 in colitis.
Fig. 4: EDNRA enhances IL-22 production by ILC3 in a cell-intrinsic manner.
Fig. 5: The AKT signaling pathway regulates NKp46+ILC3 function to confer protection against colitis.
Fig. 6: The ET-1–EDNRA axis supports ILC3 metabolic adaptation by promoting glycolysis.
Fig. 7: Restoring HIF-1α expression or administering lactate alleviates colitis symptoms in RorccreEdnrafl/fl mice.
Fig. 8: EDNRA mediates the protective effect of NKp46+ ILC3 in DSS-induced colitis.
Fig. 9: The ET-1–EDNRA axis contributes to the pathological regulation of UC.

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Acknowledgements

We would like to express our sincere gratitude to Professor C. Dong from Tsinghua University for the generous gift of Rorccre mice. We also extend our appreciation to Professor Z. Li from Southern Medical University for kindly providing the CD45.1 mice. The flow cytometry used in this work was supported by the Department of Immunology at the School of Basic Medical Sciences, Southern Medical University.

Funding

This work was supported by grants from the National Natural Science Foundation of China (Nos. 82171706 and 82471736 to YMH), the Guangdong Basic and Applied Basic Research Foundation (Nos. 2022A1515140172 and 2024A1515012897 to YMH), and the Open Fund Project of Guangdong Academy of Medical Sciences (No. YKY-KF202209 to YMH).

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  1. These authors contributed equally: Xinyao Li, Yimin Chen, Junyu He, Jian Tang.

Authors and Affiliations

  1. Pediatric Intensive Care Unit, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences); Department of Immunology, School of Basic Medical Sciences; Department of Clinical Laboratory, the Third Affiliated Hospital of Southern Medical University, Southern Medical University, Guangzhou, China

    Xinyao Li & Yumei He

  2. Department of Immunology, School of Basic Medical Sciences; Guangdong Provincial Key Laboratory of Single-cell and Extracellular Vesicles; Southern Medical University, Guangzhou, China

    Xinyao Li, Yimin Chen, Junyu He, Yizhuang Lu & Yumei He

  3. Department of Gastroenterology, the Sixth Affiliated Hospital, Sun Yat-sen University; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, the Sixth Affiliated Hospital, Sun Yat-sen University; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China

    Jian Tang

  4. Pediatric Intensive Care Unit, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University; Guangdong Provincial Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China

    Chunling Chen, Liyun Meng & Yuxiong Guo

  5. Department of Clinical Laboratory, the Third Affiliated Hospital of Southern Medical University, Southern Medical University, Guangzhou, China

    Xiaoming Lyu

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Contributions

XML, YXG, and YMH conceived the project and designed the research studies. XYL, YMC, JYH, and JT performed most of the experiments described. CLC, LYM, and YZL provided help with the technical assistance and conceptual advice in the experiments. YMH, XYL, and YMC prepared the manuscript.

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Correspondence to Xiaoming Lyu, Yuxiong Guo or Yumei He.

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The corresponding research plan and ethical approval were provided by the Clinical Trial Ethics Committee of the Sixth Affiliated Hospital of Sun Yat-sen University (Approval ID: E2022243). All animal experimental protocols were approved by the Institutional Animal Care and Use Committee of Southern Medical University Experimental Animal Ethics Committee (Approval number: L2022126).

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Li, X., Chen, Y., He, J. et al. Endothelial cell–ILC3 crosstalk via the ET-1/EDNRA axis promotes NKp46+ILC3 glycolysis to alleviate intestinal inflammation. Cell Mol Immunol 22, 1459–1477 (2025). https://doi.org/10.1038/s41423-025-01345-z

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