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. 2025 Mar;26(3):404-415.
doi: 10.1038/s41590-025-02081-2. Epub 2025 Mar 3.

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

Nian Liu #  1   2   3 , Jiacheng He #  1   3 , Yanmei Yang #  2   4 , Yunlong Wang #  2   5 , Lingwei Zhang #  2 , Ziqi Xiao  1   3 , Zhen Xiong  1 , Shangxun Zhong  1   3 , Yuwei Xu  1   3 , Yang Gu  1   3 , Jianyi Wang  1   3   6 , Yufei Lan  1   3 , Ying Du  1 , Pingping Zhu  7 , Zhi Zhang  8 , Xinjuan Fan  9   10 , Benyu Liu  11   12 , Zusen Fan  13   14
Affiliations

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

Nian Liu et al. Nat Immunol. 2025 Mar.

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.

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Conflict of interest statement

Competing interests: The authors declare no competing interests.

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