Prof. Haijun Tu’s group reports how GABAergic signaling between enteric neurons and intestinal smooth muscle promotes innate immunity and gut defense
Source：Haijun Tu
2023-08-25
The mammalian intestine is an essential organ with important physiological functions, including food digestion, nutrient absorption, xenobiotic sensing and degradation, and protection against pathogens. The normal gastrointestinal (GI) function depends on the highly coordinated responses of the enteric nervous system (ENS) and resident innate lymphoid cells in the intestine. Intestinal smooth muscle innervated by the sympathetic and parasympathetic and/or ENSs not only contracts and alters the stiffness or diameter of the GI tract, but it also plays important metabolic roles during inflammation by expressing and secreting interleukins, chemokines, and peptide growth factors. However, the role of intestinal smooth muscle cells in pathogenic defense is poorly understood.
On July 11, 2023, Haijun Tu’s group of Hunan University published a research paper entitled “GABAergic signaling between enteric neurons and intestinal smooth muscle promotes innate immunity and gut defense in Caenorhabditis elegans” in Immunity. It reveals that GABA signaling in enteric AVL/DVB neurons promoted pathogen resistance through the excitatory GABA receptor EXP-1 which specifically acted in intestinal muscle (IM). Meanwhile, the authors identified a FMRFamide (Phe-Met-Arg-Phe-NH2) neuropeptide FLP-6, secreted by IM cells, transmits intestine defense signals to the intestine. The transcriptional programs ZIP-10 and Krüppel-like factor 1 (KLF-1) act downstream of FLP-6 and converge to the PMK-1/p38 pathway to promote gut defense. The study uncover an enteric neuron-muscle-epithelium axis that may be evolutionarily conserved in mammals for the maintenance of intestinal homeostasis and defense against pathogens.
The nematode Caenorhabditis elegans (C. elegans) provides a powerful genetic model to explore the molecular and cellular mechanisms of pathogen-host interaction, host innate immunity, and intestine defense. The researcher performed a survival assay of C. elegans on the full lawn of human opportunistic pathogen P. aeruginosa PA14 to explore the role of neurotransmitters in the intestine defense of C. elegans upon pathogen infection. The researcher found that loss of GABA in unc-25 mutants exhibited enhanced susceptibility to PA14, which is likely not the secondary consequence of EMC defect of DMP in these mutants lacking GABA. Tissue specific rescue experiments confirmed that GABAergic neurotransmission between enteric AVL/DVB neurons and IM through the excitatory GABA receptor EXP-1 specifically acts in enteric muscle promoted intestine defense. Meanwhile, PMK-1/p38 is a required and downstream pathway of enteric GABAergic neurotransmission-dependent intestine defense. Further, the researchers identified that neuropeptide FLP-6 worked as a messenger molecule functions in IM and transmitted intestine defense signals from enteric GABAergic neurons to intestine epithelia for gut defense in a PMK-1/p38-dependent manner. The researcher further found that GABA/FLP-6 signaling controlled transcription factors (TFs) ZIP-10 and KLF-1 that act in parallel and redundantly to converge on PMK-1/p38 to regulate intestine defense in C. elegans.
This research reveal an anatomical axis comprising enteric AVL/DVB neurons, IM cells, and intestinal epithelial cells, which acts as a platform for a functional digestive neuron-smooth muscle-epithelium unit for the maintenance of the intestinal epithelial barrier homeostasis and integrity under physiological conditions, gut defense, and inflammatory response in intestinal infections and diseases. Targeting the digestive neuron-smooth muscle-epithelium may represent a potential strategy for the prevention of GI diseases associated with pathogen infection and inflammatory response. This study will encourage others to investigate how the nervous system regulates gut defense through enteric smooth muscle, an interesting but poorly understood question in GI immunology.
Prof. Tu group focus on studying the mechanisms of intestinal innate immunity regulated by the nervous system. As the corresponding author, Prof. Tu has published high-profile journals including Nature, Neuron, Immunity, PNAS, and Mol. Cell. Proteomics. Junqiang Liu, Pei Zhang, Zhongfan Zheng, and Muhammad Irfan Afridi from School of biology at Hunan University are co-first authors. This research has been supported by the National Natural Science Foundation of China, the National Key Research and Development Program of China, the Science, Technology and Innovation Commission of Shenzhen Municipality, and the Natural Science and Foundation of Hunan Province of China.
Article Links：https://doi.org/10.1016/j.immuni.2023.06.004
On July 11, 2023, Haijun Tu’s group of Hunan University published a research paper entitled “GABAergic signaling between enteric neurons and intestinal smooth muscle promotes innate immunity and gut defense in Caenorhabditis elegans” in Immunity. It reveals that GABA signaling in enteric AVL/DVB neurons promoted pathogen resistance through the excitatory GABA receptor EXP-1 which specifically acted in intestinal muscle (IM). Meanwhile, the authors identified a FMRFamide (Phe-Met-Arg-Phe-NH2) neuropeptide FLP-6, secreted by IM cells, transmits intestine defense signals to the intestine. The transcriptional programs ZIP-10 and Krüppel-like factor 1 (KLF-1) act downstream of FLP-6 and converge to the PMK-1/p38 pathway to promote gut defense. The study uncover an enteric neuron-muscle-epithelium axis that may be evolutionarily conserved in mammals for the maintenance of intestinal homeostasis and defense against pathogens.
The nematode Caenorhabditis elegans (C. elegans) provides a powerful genetic model to explore the molecular and cellular mechanisms of pathogen-host interaction, host innate immunity, and intestine defense. The researcher performed a survival assay of C. elegans on the full lawn of human opportunistic pathogen P. aeruginosa PA14 to explore the role of neurotransmitters in the intestine defense of C. elegans upon pathogen infection. The researcher found that loss of GABA in unc-25 mutants exhibited enhanced susceptibility to PA14, which is likely not the secondary consequence of EMC defect of DMP in these mutants lacking GABA. Tissue specific rescue experiments confirmed that GABAergic neurotransmission between enteric AVL/DVB neurons and IM through the excitatory GABA receptor EXP-1 specifically acts in enteric muscle promoted intestine defense. Meanwhile, PMK-1/p38 is a required and downstream pathway of enteric GABAergic neurotransmission-dependent intestine defense. Further, the researchers identified that neuropeptide FLP-6 worked as a messenger molecule functions in IM and transmitted intestine defense signals from enteric GABAergic neurons to intestine epithelia for gut defense in a PMK-1/p38-dependent manner. The researcher further found that GABA/FLP-6 signaling controlled transcription factors (TFs) ZIP-10 and KLF-1 that act in parallel and redundantly to converge on PMK-1/p38 to regulate intestine defense in C. elegans.
This research reveal an anatomical axis comprising enteric AVL/DVB neurons, IM cells, and intestinal epithelial cells, which acts as a platform for a functional digestive neuron-smooth muscle-epithelium unit for the maintenance of the intestinal epithelial barrier homeostasis and integrity under physiological conditions, gut defense, and inflammatory response in intestinal infections and diseases. Targeting the digestive neuron-smooth muscle-epithelium may represent a potential strategy for the prevention of GI diseases associated with pathogen infection and inflammatory response. This study will encourage others to investigate how the nervous system regulates gut defense through enteric smooth muscle, an interesting but poorly understood question in GI immunology.
Prof. Tu group focus on studying the mechanisms of intestinal innate immunity regulated by the nervous system. As the corresponding author, Prof. Tu has published high-profile journals including Nature, Neuron, Immunity, PNAS, and Mol. Cell. Proteomics. Junqiang Liu, Pei Zhang, Zhongfan Zheng, and Muhammad Irfan Afridi from School of biology at Hunan University are co-first authors. This research has been supported by the National Natural Science Foundation of China, the National Key Research and Development Program of China, the Science, Technology and Innovation Commission of Shenzhen Municipality, and the Natural Science and Foundation of Hunan Province of China.
Article Links：https://doi.org/10.1016/j.immuni.2023.06.004
