GABAergic Synapses Suppress Intestinal Innate Immunity Via Insulin Signaling in

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2021 May 11

PMID 33972423

Citations 13

Authors

Zhongfan Zheng

Xiumei Zhang

Junqiang Liu

Ping He

Shan Zhang

Yongning Zhang

Jie Gao

Shengmei Yang

Na Kang

Muhammad Irfan Afridi

Shangbang Gao

Chunhong Chen

Haijun Tu

Affiliations

Soon will be listed here.

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 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 GABAR-deficient mutant compared with wild-type animals. with knockdown or loss of function exhibited enhanced resistance to 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.

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References

Bamber B, Beg A, Twyman R, Jorgensen E . The Caenorhabditis elegans unc-49 locus encodes multiple subunits of a heteromultimeric GABA receptor. J Neurosci. 1999; 19(13):5348-59. PMC: 6782323. View

Tang H, Pang S . Proline Catabolism Modulates Innate Immunity in Caenorhabditis elegans. Cell Rep. 2016; 17(11):2837-2844. DOI: 10.1016/j.celrep.2016.11.038. View

Evans E, Kawli T, Tan M . Pseudomonas aeruginosa suppresses host immunity by activating the DAF-2 insulin-like signaling pathway in Caenorhabditis elegans. PLoS Pathog. 2008; 4(10):e1000175. PMC: 2568960. DOI: 10.1371/journal.ppat.1000175. View

Shivers R, Pagano D, Kooistra T, Richardson C, Reddy K, Whitney J . Phosphorylation of the conserved transcription factor ATF-7 by PMK-1 p38 MAPK regulates innate immunity in Caenorhabditis elegans. PLoS Genet. 2010; 6(4):e1000892. PMC: 2848548. DOI: 10.1371/journal.pgen.1000892. View

Alper S, McBride S, Lackford B, Freedman J, Schwartz D . Specificity and complexity of the Caenorhabditis elegans innate immune response. Mol Cell Biol. 2007; 27(15):5544-53. PMC: 1952075. DOI: 10.1128/MCB.02070-06. View

Gibson D . Enzymatic assembly of overlapping DNA fragments. Methods Enzymol. 2011; 498:349-61. PMC: 7149801. DOI: 10.1016/B978-0-12-385120-8.00015-2. View

Lin K, Hsin H, Libina N, Kenyon C . Regulation of the Caenorhabditis elegans longevity protein DAF-16 by insulin/IGF-1 and germline signaling. Nat Genet. 2001; 28(2):139-45. DOI: 10.1038/88850. View

Kim J, Kim Y, Lee H, Jin H, Neupane C, Kim S . GABAergic signaling linked to autophagy enhances host protection against intracellular bacterial infections. Nat Commun. 2018; 9(1):4184. PMC: 6180030. DOI: 10.1038/s41467-018-06487-5. View

McIntire S, Reimer R, Schuske K, EDWARDS R, Jorgensen E . Identification and characterization of the vesicular GABA transporter. Nature. 1997; 389(6653):870-6. DOI: 10.1038/39908. View

10.

Fernandes De Abreu D, Caballero A, Fardel P, Stroustrup N, Chen Z, Lee K . An insulin-to-insulin regulatory network orchestrates phenotypic specificity in development and physiology. PLoS Genet. 2014; 10(3):e1004225. PMC: 3967928. DOI: 10.1371/journal.pgen.1004225. View

11.

Jin Y, Hoskins R, Horvitz H . Control of type-D GABAergic neuron differentiation by C. elegans UNC-30 homeodomain protein. Nature. 1994; 372(6508):780-3. DOI: 10.1038/372780a0. View

12.

Zheng S, Chiu H, Boudreau J, Papanicolaou T, Bendena W, Chin-Sang I . A functional study of all 40 insulin-like peptides. J Biol Chem. 2018; 293(43):16912-16922. PMC: 6204898. DOI: 10.1074/jbc.RA118.004542. View

13.

Jin Z, Kumar Mendu S, Birnir B . GABA is an effective immunomodulatory molecule. Amino Acids. 2011; 45(1):87-94. PMC: 3680704. DOI: 10.1007/s00726-011-1193-7. View

14.

Sieburth D, Chng Q, Dybbs M, Tavazoie M, Kennedy S, Wang D . Systematic analysis of genes required for synapse structure and function. Nature. 2005; 436(7050):510-7. DOI: 10.1038/nature03809. View

15.

Kim B, Suo B, Emmons S . Gene Function Prediction Based on Developmental Transcriptomes of the Two Sexes in C. elegans. Cell Rep. 2016; 17(3):917-928. PMC: 5656000. DOI: 10.1016/j.celrep.2016.09.051. View

16.

Irazoqui J, Urbach J, Ausubel F . Evolution of host innate defence: insights from Caenorhabditis elegans and primitive invertebrates. Nat Rev Immunol. 2009; 10(1):47-58. PMC: 2965059. DOI: 10.1038/nri2689. View

17.

Labed S, Wani K, Jagadeesan S, Hakkim A, Najibi M, Irazoqui J . Intestinal Epithelial Wnt Signaling Mediates Acetylcholine-Triggered Host Defense against Infection. Immunity. 2018; 48(5):963-978.e3. PMC: 5959051. DOI: 10.1016/j.immuni.2018.04.017. View

18.

Cao X, Kajino-Sakamoto R, Doss A, Aballay A . Distinct Roles of Sensory Neurons in Mediating Pathogen Avoidance and Neuropeptide-Dependent Immune Regulation. Cell Rep. 2017; 21(6):1442-1451. PMC: 5726787. DOI: 10.1016/j.celrep.2017.10.050. View

19.

Meisel J, Panda O, Mahanti P, Schroeder F, Kim D . Chemosensation of bacterial secondary metabolites modulates neuroendocrine signaling and behavior of C. elegans. Cell. 2014; 159(2):267-80. PMC: 4194030. DOI: 10.1016/j.cell.2014.09.011. View

20.

Fuhrman L, Goel A, Smith J, Shianna K, Aballay A . Nucleolar proteins suppress Caenorhabditis elegans innate immunity by inhibiting p53/CEP-1. PLoS Genet. 2009; 5(9):e1000657. PMC: 2734340. DOI: 10.1371/journal.pgen.1000657. View