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

被引：1

作者：

Liu, Nian ^{[1
,2
,3
]}

He, Jiacheng ^{[1
,3
]}

Yang, Yanmei ^{[2
,4
]}

Wang, Yunlong ^{[2
,5
]}

Zhang, Lingwei ^{[2
]}

Xiao, Ziqi ^{[1
,3
]}

Xiong, Zhen ^{[1
]}

Zhong, Shangxun ^{[1
,3
]}

Xu, Yuwei ^{[1
,3
]}

Gu, Yang ^{[1
,3
]}

Wang, Jianyi ^{[1
,3
,6
]}

Lan, Yufei ^{[1
,3
]}

Du, Ying ^{[1
]}

Zhu, Pingping ^{[7
]}

Zhang, Zhi ^{[8
]}

Fan, Xinjuan ^{[2
,9
]}

Liu, Benyu ^{[2
,4
]}

Fan, Zusen ^{[1
,3
]}

机构：

[1] Chinese Acad Sci, Inst Biophys, Key Lab RNA Sci & Engn, Key Lab Epigenet Regulat & Intervent, Beijing, Peoples R China

[2] Zhengzhou Univ, Acad Med Sci, Tianjian Lab Adv Biomed Sci, Zhengzhou, Peoples R China

[3] Univ Chinese Acad Sci, Beijing, Peoples R China

[4] Henan Acad Innovat Med Sci, Inst Infect & Immun, Zhengzhou, Peoples R China

[5] Zhengzhou Univ, Dept Radiat Oncol, Henan Prov Key Lab Radiat Med, Affiliated Hosp 1, Zhengzhou, Peoples R China

[6] Beijing Inst Drug Control, Beijing, Peoples R China

[7] Zhengzhou Univ, Sch Life Sci, Zhengzhou, Peoples R China

[8] Univ Sci & Technol China, Div Life Sci & Med, Hefei Natl Lab Phys Sci Microscale, Affiliated Hosp USTC 1,Dept Anesthesiol & Pain Med, Hefei, Peoples R China

[9] Zhengzhou Univ, Dept Pathol, Henan Prov Key Lab Radiat Med, Affiliated Hosp 1, Zhengzhou, Peoples R China

来源：

NATURE IMMUNOLOGY | 2025年 / 26卷 / 03期

基金：

国家重点研发计划; 中国国家自然科学基金;

关键词：

INNATE LYMPHOID-CELLS; MODEL;

D O I：

10.1038/s41590-025-02081-2

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

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 gamma-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-beta 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-beta-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.

引用

页码：404 / 415

页数：33