State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Biology, Hunan University, Changsha 410082, Hunan, China.
State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Biology, Hunan University, Changsha 410082, Hunan, China.
Immunity. 2023 Jul 11;56(7):1515-1532.e9. doi: 10.1016/j.immuni.2023.06.004.
The nervous system is critical for intestinal homeostasis and function, but questions remain regarding its impact on gut immune defense. By screening the major neurotransmitters of C. elegans, we found that γ-aminobutyric acid (GABA) deficiency enhanced susceptibility to pathogenic Pseudomonas aeruginosa PA14 infection. GABAergic signaling between enteric neurons and intestinal smooth muscle promoted gut defense in a PMK-1/p38-dependent, but IIS/DAF-16- and DBL-1/TGF-β-independent, pathway. Transcriptomic profiling revealed that the neuropeptide, FLP-6, acted downstream of enteric GABAergic signaling. Further data determined that FLP-6 was expressed and secreted by intestinal smooth muscle cells and functioned as a paracrine molecule on the intestinal epithelium. FLP-6 suppressed the transcription factors ZIP-10 and KLF-1 that worked in parallel and converged to the PMK-1/p38 pathway in the intestinal epithelia for innate immunity and gut defense. Collectively, these findings uncover an enteric neuron-muscle-epithelium axis that may be evolutionarily conserved in higher organisms.
神经系统对肠道稳态和功能至关重要，但关于其对肠道免疫防御的影响仍存在疑问。通过筛选秀丽隐杆线虫的主要神经递质，我们发现γ-氨基丁酸（GABA）缺乏会增加对致病性铜绿假单胞菌 PA14 感染的易感性。肠神经元和肠道平滑肌之间的 GABA 能信号通过 PMK-1/p38 依赖性、但 IIS/DAF-16 和 DBL-1/TGF-β 非依赖性途径促进肠道防御。转录组分析显示，神经肽 FLP-6 在下消化道 GABA 能信号转导的下游发挥作用。进一步的数据确定，FLP-6 由肠道平滑肌细胞表达和分泌，并作为旁分泌分子在肠道上皮细胞上发挥作用。FLP-6 抑制转录因子 ZIP-10 和 KLF-1，它们平行工作并汇聚到肠道上皮细胞中的 PMK-1/p38 途径，以实现先天免疫和肠道防御。总的来说，这些发现揭示了一个可能在高等生物中进化保守的肠神经元-肌肉-上皮轴。
