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

Proc Natl Acad Sci U S A. 2021 May 18;118(20):e2021063118. doi: 10.1073/pnas.2021063118.

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.

Keywords: GABAergic synapse; innate immunity; insulin signaling; intestine; muscle.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans / immunology*
  • Caenorhabditis elegans / microbiology
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / immunology*
  • Caenorhabditis elegans Proteins / physiology
  • GABAergic Neurons / immunology
  • GABAergic Neurons / metabolism
  • GABAergic Neurons / microbiology
  • Host-Pathogen Interactions / immunology
  • Humans
  • Immunity, Innate / genetics
  • Immunity, Innate / immunology*
  • Insulin / immunology*
  • Insulin / metabolism
  • Intestines / immunology*
  • Intestines / microbiology
  • Intestines / physiology
  • Mutation
  • Neuromuscular Junction / immunology
  • Neuromuscular Junction / microbiology
  • Neuromuscular Junction / physiology
  • Pseudomonas aeruginosa / immunology
  • Pseudomonas aeruginosa / physiology
  • Receptors, GABA-A / genetics
  • Receptors, GABA-A / immunology*
  • Receptors, GABA-A / physiology
  • Signal Transduction / immunology
  • Synapses / immunology*
  • Synapses / microbiology
  • Synapses / physiology
  • Synaptic Transmission / genetics
  • Synaptic Transmission / immunology
  • Synaptic Transmission / physiology

Substances

  • Caenorhabditis elegans Proteins
  • Insulin
  • Receptors, GABA-A
  • Unc-49 protein, C elegans