GABAergic synapses suppress intestinal innate immunity via insulin signaling in Caenorhabditis elegans

Abstract

GABAergic neurotransmission constitutes a major inhibitory signaling mechanism that plays crucial roles in central nervous system physiology and immune cell immunomodulation. However, its roles in innate immunity remain unclear. Here, we report that deficiency in the GABAergic neuromuscular junctions (NMJs) of Caenorhabditis elegans results in enhanced resistance to pathogens, whereas pathogen infection enhances the strength of GABAergic transmission. GABAergic synapses control innate immunity in a manner dependent on the FOXO/DAF-16 but not the p38/PMK-1 pathway. Our data reveal that the insulin-like peptide INS-31 level was dramatically decreased in the GABAergic NMJ GABAAR-deficient unc-49 mutant compared with wild-type animals. C. elegans with ins-31 knockdown or loss of function exhibited enhanced resistance to Pseudomonas aeruginosa PA14 exposure. INS-31 may act downstream of GABAergic NMJs and in body wall muscle to control intestinal innate immunity in a cell-nonautonomous manner. Our results reveal a signaling axis of synapse–muscular insulin–intestinal innate immunity in vivo.

The mRNA and miRNA profiles of goat bronchial epithelial cells stimulated by Pasteurella multocida strains of serotype A and D

“…In the P. multocida strain serotype A-stimulated group, the significant KEGG pathways related to immunity were GABAergic synapse (ko04727) and the Toll-like receptor signaling pathway (ko04620). A recent study reported that GABAergic neurotransmission plays an important role in central nervous system physiology and cellular immune regulation, and revealed a new “synapse—muscular insulin—intestinal innate immunity” signaling axis, which may help to maintain immunological homeostasis and promote host survival ( Zheng et al, 2021 ). As shown in Fig.…”

Gut neuroendocrine signaling regulates synaptic assembly in C. elegans

“…Gut–brain communication plays an important role in coping with unfavorite environmental conditions. For example, under stress conditions, intestinal signaling regulates locomotion by modulating synaptic transmission at the neuromuscular junctions (D'Ercole et al , 2002; Staab et al , 2013; Zheng et al , 2021). Intestinal infections can affect the host's learning and behavior by neuroendocrine signaling pathways (Singh & Aballay, 2019).…”

Gut microbial GABAergic signaling imprints alveolar macrophages and pulmonary response to viral infection associated with psychological stress

“…Inspired by these ndings, we further identify GABA, a gut bacteria-derived metabolite, as a central signaling message mediating this neuro-immune regulation. GABA is a well-de ned inhibitory neurotransmitter, as well as a newly discovered immune regulator [51][52][53]. To con rm that GABA is prominently generated by intestinal bacteria rather tha host cells like B cells, neural and pancreatic cells [16,17], we garnered multiple lines of evidences: Firstly, depletion of intestinal microbiome led to a remarkable decrease in serum GABA level in non-stressed mice, directly linking GABA with gut bacteria; Secondly, fecal level of GAD, the enzyme responsible for catalyzing glutamate decarboxylation and GABA secretion in bacteria, was decreased in stressed mice relative to healthy animals; Thirdly, correlating with stress-induced suppression of GABA-generating bacteria, transplantation of stress-modi ed but not "untouched" gut microbiome caused a marked reduction of GABA release; Moreover, the level of GABA in stressed mice was greatly elevated by supplementation of Lactobacillus, preceding signi cantly improved lung pathology upon IAV infection.…”