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1.
Immunity ; 56(7): 1515-1532.e9, 2023 07 11.
Article in English | MEDLINE | ID: mdl-37437538

ABSTRACT

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-ß-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.


Subject(s)
Caenorhabditis elegans , Neurons , Animals , Muscle, Smooth , Signal Transduction , Immunity, Innate
2.
Int Immunol ; 35(4): 181-196, 2023 04 04.
Article in English | MEDLINE | ID: mdl-36409527

ABSTRACT

Innate immunity is the first line of host defense against pathogenic invasion in metazoans. The transcription factor basic leucine zipper transcriptional factor ATF-like 3 (BATF3) plays a crucial role in the development of conventional dendritic cells and the program of CD8 + T cell survival and memory, but the role of BATF3 in innate immune responses remains unclear. Here, we show an evolutionarily conserved basic-region leucine zipper (bZIP) transcription factor BATF3/ZIP-10 suppresses innate immune response through repressing the p38/PMK-1 mitogen-activated protein kinase (MAPK) pathway in vitro and in vivo. The worm mutant lacking the Caenorhabditis elegans homolog BATF3, ZIP-10, exhibited enhanced resistance to PA14 infection, which was completely rescued by transgenic expression of either endogenous zip-10 or mouse or human Batf3 cDNA driven by the worm zip-10 promoter. ZIP-10 expression was inhibited by a microRNA miR-60 that was downregulated upon PA14 infection. Moreover, the level of phosphorylated but not total PMK-1/p38 was attenuated by ZIP-10 and stimulated by miR-60. The human HEK293 cells with Batf3 overexpression or RNA-interference knockdown exhibited a reduction or increase of the cell viability upon Pseudomonas aeruginosa PA14 infection, respectively. The overexpression of either worm ZIP-10 or human BATF3 abolished the activation of p38 and inhibited the expression of antimicrobial peptides and cytokine genes in HEK293 cells. Our findings indicate that the genetic transcriptional program of the evolutionally conserved bZIP transcription factor BATF3/ZIP-10 suppresses innate immunity by attenuating the p38 MAPK signaling activity, which expands our understanding of the pathological mechanisms underlying relevant infectious diseases.


Subject(s)
Caenorhabditis elegans Proteins , MicroRNAs , Pseudomonas Infections , Animals , Humans , Mice , Basic-Leucine Zipper Transcription Factors/genetics , Basic-Leucine Zipper Transcription Factors/metabolism , Caenorhabditis elegans Proteins/genetics , Caenorhabditis elegans Proteins/metabolism , HEK293 Cells , Caenorhabditis elegans/genetics , Caenorhabditis elegans/metabolism , Immunity, Innate , Transcription Factors/metabolism , p38 Mitogen-Activated Protein Kinases/metabolism , MicroRNAs/genetics , Mitogen-Activated Protein Kinases/genetics , Mitogen-Activated Protein Kinases/metabolism
3.
ACS Chem Neurosci ; 13(23): 3427-3437, 2022 12 07.
Article in English | MEDLINE | ID: mdl-36441912

ABSTRACT

Innate immunity is an ancient and evolutionarily conserved system that constitutes the first line of host defense against invading microbes. We previously determined that the GABAergic neuromuscular junction (NMJ) suppresses intestinal innate immunity via muscular insulin signaling. Here, we found that a muscular mitochondrial oxidative phosphorylation pathway of Caenorhabditis elegans is involved in GABAergic NMJs-mediated intestinal defense. Deficiency in GABAergic neurotransmission increases reactive oxygen species (ROS) abundance and inhibits the nuclear translocation of SKN-1, whereas exogenous GABA administration represses it. SKN-1 is an important transcription factor involved in oxidative stress and the innate immune response. Moreover, deficiency in GABAergic postsynaptic UNC-49/GABAAR robustly promotes the mitochondrial function of GABAergic postsynaptic muscle cells, which may contribute to the muscular ROS decrease and intestinal SKN-1 suppression, ultimately inhibiting the intestinal defense of C. elegans. Our findings reveal a potential role of muscle mitochondrial ROS in intestinal defense in vivo and expand our understanding of mechanisms of intestinal innate immunity.


Subject(s)
Caenorhabditis elegans , Neuromuscular Junction , Animals
4.
Front Immunol ; 12: 744454, 2021.
Article in English | MEDLINE | ID: mdl-34804026

ABSTRACT

Innate immunity is the first line of host defense against pathogen infection in metazoans. However, the molecular mechanisms of the complex immune regulatory network are not fully understood. Based on a transcriptome profiling of the nematode Caenorhabditis elegans, we found that a bZIP transcription factor ZIP-11 was up-regulated upon Pseudomonas aeruginosa PA14 infection. The tissue specific RNAi knock-down and rescue data revealed that ZIP-11 acts in intestine to promote host resistance against P. aeruginosa PA14 infection. We further showed that intestinal ZIP-11 regulates innate immune response through constituting a feedback loop with the conserved PMK-1/p38 mitogen-activated protein signaling pathway. Intriguingly, ZIP-11 interacts with a CCAAT/enhancer-binding protein, CEBP-2, to mediate the transcriptional response to P. aeruginosa PA14 infection independently of PMK-1/p38 pathway. In addition, human homolog ATF4 can functionally substitute for ZIP-11 in innate immune regulation of C. elegans. Our findings indicate that the ZIP-11/ATF4 genetic program activates local innate immune response through conserved PMK-1/p38 and CEBP-2/C/EBPγ immune signals in C. elegans, raising the possibility that a similar process may occur in other organisms.


Subject(s)
Basic-Leucine Zipper Transcription Factors/immunology , Caenorhabditis elegans Proteins/immunology , Immunity, Innate/immunology , Activating Transcription Factor 4/immunology , Animals , Animals, Genetically Modified , Caenorhabditis elegans/immunology , Humans
5.
Proc Natl Acad Sci U S A ; 118(20)2021 05 18.
Article in English | MEDLINE | ID: mdl-33972423

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.


Subject(s)
Caenorhabditis elegans Proteins/immunology , Caenorhabditis elegans/immunology , Immunity, Innate/immunology , Insulin/immunology , Intestines/immunology , Receptors, GABA-A/immunology , Synapses/immunology , Adult , Animals , Caenorhabditis elegans/genetics , Caenorhabditis elegans/microbiology , Caenorhabditis elegans Proteins/genetics , Caenorhabditis elegans Proteins/physiology , GABAergic Neurons/immunology , GABAergic Neurons/metabolism , GABAergic Neurons/microbiology , Host-Pathogen Interactions/immunology , Humans , Immunity, Innate/genetics , Insulin/metabolism , 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/physiology , Signal Transduction/immunology , Synapses/microbiology , Synapses/physiology , Synaptic Transmission/genetics , Synaptic Transmission/immunology , Synaptic Transmission/physiology
6.
Anal Chem ; 91(14): 8762-8766, 2019 07 16.
Article in English | MEDLINE | ID: mdl-31241905

ABSTRACT

Noble metals with strong plasmons have been widely used as enhancement substrates for molecule identification. However, cyanide, a toxic and important signaling molecule with a corrosive nature to noble metals, makes direct recognition challenging. Herein a novel superstable magnetic graphene-isolated AuCo nanocrystal (MACG) has been designed. Such graphene isolation enables superior stability without corrosion. Moreover, unexpectedly, although graphene isolated direct contact between Au and cyanide, their interaction was transferable and remained, which gifted MACGs direct cyanide capture capability with no specific ligands needed. Density functional theory calculations and natural bond orbital analysis indicated that the graphene isolation only slightly affected the charge transfer and that a relatively strong interaction was maintained between Au and cyanide. MACGs were utilized for efficient cyanide capture and clearance in various hydrologic environments and sensitive in vivo cyanide capture in C. elegans infected with P. aeruginosa, a pathogen with cyanide as the biomarker, indicating promise for various applications.


Subject(s)
Cobalt/chemistry , Cyanides/isolation & purification , Gold/chemistry , Graphite/chemistry , Nanoparticles/chemistry , Animals , Caenorhabditis elegans/microbiology , HeLa Cells , Humans , Magnets/chemistry
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