近日，中国科学院生物物理研究所范祖森及其小组发现，肠内GABA能神经元来源的γ-氨基丁酸启动Igfbp7的表达以维持ILC3的稳态。相关论文发表在2025年3月3日出版的《自然—免疫学》杂志上。

课题组人员发现肠内GABA能神经元源性神经递质γ-氨基丁酸（GABA）以依赖GABA受体Gabbr1和Gabbr2的方式抑制ILC3s的增殖和IL-17A的产生。Gabbr1的条件缺失或GABA能神经元的消融导致IL-17A的产生增加和结肠炎的加重。从机制上讲，GABA抑制ILC3s中转录因子C/EBP-β的LIP亚型的表达，从而抑制Igfbp7的转录，而Igfbp7编码分泌因子Igfbp7。自分泌Igfbp7信号通过受体Igf1R抑制ILC3增殖和IL-17A的产生。通过GABA-C/EBP-β-IGFBP7通路抑制信号与炎症性肠病（IBD）患者肠道炎症的严重程度高度相关。总的来说，他们的发现描述了维持肠道免疫稳态的重要分子机制。

据悉，神经元信号已成为调节第3组先天淋巴样细胞（ILC3）反应和组织稳态的关键因素，但这种调节的分子机制在很大程度上仍然是未知的。

附：英文原文

Title: Enteric GABAergic neuron-derived γ-aminobutyric acid initiates expression of Igfbp7 to sustain ILC3 homeostasis

Author: Liu, Nian, He, Jiacheng, Yang, Yanmei, Wang, Yunlong, Zhang, Lingwei, Xiao, Ziqi, Xiong, Zhen, Zhong, Shangxun, Xu, Yuwei, Gu, Yang, Wang, Jianyi, Lan, Yufei, Du, Ying, Zhu, Pingping, Zhang, Zhi, Fan, Xinjuan, Liu, Benyu, Fan, Zusen

Issue&Volume: 2025-03-03

Abstract: Neuronal signals have emerged as critical factors that regulate group 3 innate lymphoid cell (ILC3) response and tissue homeostasis, but the molecular mechanisms underlying this regulation remain largely elusive. Here, we identified that the enteric GABAergic neuron-derived neurotransmitter γ-aminobutyric acid (GABA) inhibited proliferation and IL-17A production in ILC3s in a manner dependent on the GABA receptors Gabbr1 and Gabbr2. Conditional deletion of Gabbr1 or ablation of GABAergic neurons caused increased IL-17A production and aggravated colitis. Mechanistically, GABA suppressed the expression of the LIP isoform of the transcription factor C/EBP-β in ILC3s, which repressed the transcription of Igfbp7, which encodes the secreted factor Igfbp7. Autocrine Igfbp7 signaling through the receptor Igf1R inhibited ILC3 proliferation and IL-17A production. Suppression of signaling through the GABA-C/EBP-β-IGFBP7 pathway highly correlated with severity of intestinal inflammation in patients with inflammatory bowel disease (IBD). Collectively, our findings describe an important molecular mechanism underlying the maintenance of gut immune homeostasis.

DOI: 10.1038/s41590-025-02081-2

Source: https://www.nature.com/articles/s41590-025-02081-2