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

2021 ◽  
Vol 118 (20) ◽  
pp. e2021063118
Author(s):  
Zhongfan Zheng ◽  
Xiumei Zhang ◽  
Junqiang Liu ◽  
Ping He ◽  
Shan Zhang ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Caenorhabditis Elegans ◽  
Immune Cell ◽  
Neuromuscular Junctions ◽  
Loss Of Function ◽  
Signaling Mechanism ◽  
Gabaergic Neurotransmission ◽  
Enhanced Resistance ◽  
Gabaergic Synapses

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.

scholarly journals Administration of cardiac mesenchymal cells modulates innate immunity in the acute phase of myocardial infarction in mice

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Yi Kang ◽  
Marjan Nasr ◽  
Yiru Guo ◽  
Shizuka Uchida ◽  
Tyler Weirick ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Innate Immunity ◽  
Mechanism Of Action ◽  
Cell Activation ◽  
Cell Function ◽  
Immune Cell ◽  
Mesenchymal Cell ◽  
Cell Types

Abstract Although cardiac mesenchymal cell (CMC) therapy mitigates post-infarct cardiac dysfunction, the underlying mechanisms remain unidentified. It is acknowledged that donor cells are neither appreciably retained nor meaningfully contribute to tissue regeneration—suggesting a paracrine-mediated mechanism of action. As the immune system is inextricably linked to wound healing/remodeling in the ischemically injured heart, the reparative actions of CMCs may be attributed to their immunoregulatory properties. The current study evaluated the consequences of CMC administration on post myocardial infarction (MI) immune responses in vivo and paracrine-mediated immune cell function in vitro. CMC administration preferentially elicited the recruitment of cell types associated with innate immunity (e.g., monocytes/macrophages and neutrophils). CMC paracrine signaling assays revealed enhancement in innate immune cell chemoattraction, survival, and phagocytosis, and diminished pro-inflammatory immune cell activation; data that identifies and catalogues fundamental immunomodulatory properties of CMCs, which have broad implications regarding the mechanism of action of CMCs in cardiac repair.

scholarly journals Stimulation of Innate Immunity byIn VivoCyclic di-GMP Synthesis Using Adenovirus

2014 ◽  
Vol 21 (11) ◽  
pp. 1550-1559 ◽  
Author(s):  
Benjamin J. Koestler ◽  
Sergey S. Seregin ◽  
David P. W. Rastall ◽  
Yasser A. Aldhamen ◽  
Sarah Godbehere ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Mammalian Cells ◽  
Immune Cell ◽  
Innate Immune ◽  
Host Cells ◽  
Content Type ◽  
Cytokines And Chemokines ◽  
Novel Approach

ABSTRACTThe bacterial second messenger cyclic di-GMP (c-di-GMP) stimulates inflammation by initiating innate immune cell recruitment and triggering the release of proinflammatory cytokines and chemokines. These properties make c-di-GMP a promising candidate for use as a vaccine adjuvant, and numerous studies have demonstrated that administration of purified c-di-GMP with different antigens increases protection against infection in animal models. Here, we have developed a novel approach to produce c-di-GMP inside host cells as an adjuvant to exploit a host-pathogen interaction and initiate an innate immune response. We have demonstrated that c-di-GMP can be synthesizedin vivoby transducing a diguanylate cyclase (DGC) gene into mammalian cells using an adenovirus serotype 5 (Ad5) vector. Expression of DGC led to the production of c-di-GMPin vitroandin vivo, and this was able to alter proinflammatory gene expression in murine tissues and increase the secretion of numerous cytokines and chemokines when administered to animals. Furthermore, coexpression of DGC modestly increased T-cell responses to aClostridium difficileantigen expressed from an adenovirus vaccine, although no significant differences in antibody titers were observed. This adenovirus c-di-GMP delivery system offers a novel method to administer c-di-GMP as an adjuvant to stimulate innate immunity during vaccination.

scholarly journals Normal Formation of a Subset of Intestinal Granules in Caenorhabditis elegans Requires ATP-binding Cassette Transporters HAF-4 and HAF-9, Which Are Highly Homologous to Human Lysosomal Peptide Transporter TAP-Like

2009 ◽  
Vol 20 (12) ◽  
pp. 2979-2990 ◽  
Author(s):  
Hiromi Kawai ◽  
Takahiro Tanji ◽  
Hirohisa Shiraishi ◽  
Mitsuo Yamada ◽  
Ryoko Iijima ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Fluorescent Protein ◽  
Model Organism ◽  
Physiological Role ◽  
Peptide Transporter ◽  
Atp Binding ◽  
Loss Of Function ◽  
Specific Expression ◽  
Atp Binding Cassette

TAP-like (TAPL; ABCB9) is a half-type ATP-binding cassette (ABC) transporter that localizes in lysosome and putatively conveys peptides from cytosol to lysosome. However, the physiological role of this transporter remains to be elucidated. Comparison of genome databases reveals that TAPL is conserved in various species from a simple model organism, Caenorhabditis elegans, to mammals. C. elegans possesses homologous TAPL genes: haf-4 and haf-9. In this study, we examined the tissue-specific expression of these two genes and analyzed the phenotypes of the loss-of-function mutants for haf-4 and haf-9 to elucidate the in vivo function of these genes. Both HAF-4 and HAF-9 tagged with green fluorescent protein (GFP) were mainly localized on the membrane of nonacidic but lysosome-associated membrane protein homologue (LMP-1)-positive intestinal granules from larval to adult stage. The mutants for haf-4 and haf-9 exhibited granular defects in late larval and young adult intestinal cells, associated with decreased brood size, prolonged defecation cycle, and slow growth. The intestinal granular phenotype was rescued by the overexpression of the GFP-tagged wild-type protein, but not by the ATP-unbound form of HAF-4. These results demonstrate that two ABC transporters, HAF-4 and HAF-9, are related to intestinal granular formation and some other physiological aspects.

scholarly journals Polyphenols from Blumea laciniata Extended the Lifespan and Enhanced Resistance to Stress in Caenorhabditis elegans via the Insulin Signaling Pathway

Antioxidants ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 1744
Author(s):  
Tao Chen ◽  
Siyuan Luo ◽  
Xiaoju Wang ◽  
Yiling Zhou ◽  
Yali Dai ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Signaling Pathway ◽  
Relevant Literature ◽  
Folk Medicine ◽  
Ageing Effect ◽  
C Elegans ◽  
Enhanced Resistance ◽  
Resistance To Stress

Blumea laciniata is widely used as a folk medicine in Asia, but relevant literature on it is rarely reported. We confirmed that polyphenol extract (containing chlorogenic acid, rutin, and luteolin-4-O-glucoside) from B. laciniata (EBL) showed strong antioxidant ability in vitro. Hence, in this work, we applied Caenorhabditis elegans to further investigate the antioxidant and anti-ageing abilities of EBL in vivo. The results showed that EBL enhanced the survival of C. elegans under thermal stress by 12.62% and sharply reduced the reactive oxygen species level as well as the content of malonaldehyde. Moreover, EBL increased the activities of antioxidant enzymes such as catalase and superoxide dismutase. Additionally, EBL promoted DAF-16, a transcription factor, into the nucleus. Besides, EBL extended the lifespan of C. elegans by 17.39%, showing an anti-ageing effect. Different mutants indicated that the insulin/IGF-1 signaling pathway participated in the antioxidant and anti-ageing effect of EBL on C. elegans.

scholarly journals Hypoexcitability precedes denervation in the large fast-contracting motor units in two unrelated mouse models of ALS

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
María de Lourdes Martínez-Silva ◽  
Rebecca D Imhoff-Manuel ◽  
Aarti Sharma ◽  
CJ Heckman ◽  
Neil A Shneider ◽  
...  
Keyword(s):  
Motor Unit ◽  
Mouse Models ◽  
Neuromuscular Junctions ◽  
Motor Units ◽  
Loss Of Function ◽  
Disease Markers ◽  
Physiological Type ◽  
Lateral Sclerosis ◽  
Motoneuron Degeneration

Hyperexcitability has been suggested to contribute to motoneuron degeneration in amyotrophic lateral sclerosis (ALS). If this is so, and given that the physiological type of a motor unit determines the relative susceptibility of its motoneuron in ALS, then one would expect the most vulnerable motoneurons to display the strongest hyperexcitability prior to their degeneration, whereas the less vulnerable should display a moderate hyperexcitability, if any. We tested this hypothesis in vivo in two unrelated ALS mouse models by correlating the electrical properties of motoneurons with their physiological types, identified based on their motor unit contractile properties. We found that, far from being hyperexcitable, the most vulnerable motoneurons become unable to fire repetitively despite the fact that their neuromuscular junctions were still functional. Disease markers confirm that this loss of function is an early sign of degeneration. Our results indicate that intrinsic hyperexcitability is unlikely to be the cause of motoneuron degeneration.

scholarly journals Fibroblast membrane-camouflaged nanoparticles for inflammation treatment in the early stage

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Lizhong Sun ◽  
Libang He ◽  
Wei Wu ◽  
Li Luo ◽  
Mingyue Han ◽  
...  
Keyword(s):  
Cell Membrane ◽  
Immune Cell ◽  
Early Stage ◽  
Specific Treatment ◽  
Cell Types ◽  
Loss Of Function ◽  
Tissue Repair And Regeneration ◽  
Inflammatory Conditions

AbstractUnrestrained inflammation is harmful to tissue repair and regeneration. Immune cell membrane-camouflaged nanoparticles have been proven to show promise as inflammation targets and multitargeted inflammation controls in the treatment of severe inflammation. Prevention and early intervention of inflammation can reduce the risk of irreversible tissue damage and loss of function, but no cell membrane-camouflaged nanotechnology has been reported to achieve stage-specific treatment in these conditions. In this study, we investigated the prophylactic and therapeutic efficacy of fibroblast membrane-camouflaged nanoparticles for topical treatment of early inflammation (early pulpitis as the model) with the help of in-depth bioinformatics and molecular biology investigations in vitro and in vivo. Nanoparticles have been proven to act as sentinels to detect and competitively neutralize invasive Escherichia coli lipopolysaccharide (E. coli LPS) with resident fibroblasts to effectively inhibit the activation of intricate signaling pathways. Moreover, nanoparticles can alleviate the secretion of multiple inflammatory cytokines to achieve multitargeted anti-inflammatory effects, attenuating inflammatory conditions in the early stage. Our work verified the feasibility of fibroblast membrane-camouflaged nanoparticles for inflammation treatment in the early stage, which widens the potential cell types for inflammation regulation.

scholarly journals Ankyrin-G Regulates Forebrain Connectivity and Network Synchronization via Interaction with GABARAP

2018 ◽  
Author(s):  
AD Nelson ◽  
RN Caballero-Florán ◽  
JC Rodríguez Díaz ◽  
J Li ◽  
K Chen ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Pyramidal Cell ◽  
Pyramidal Neurons ◽  
Loss Of Function ◽  
Network Synchronization ◽  
Receptor Associated Protein ◽  
Ankyrin G ◽  
Neuropsychiatric Diseases ◽  
Gabaergic Synapses

ABSTRACTGABAergic circuits are critical for the synchronization and higher order function of brain networks, and defects in this circuitry are linked to neuropsychiatric diseases, including bipolar disorder, schizophrenia, and autism. Work in cultured neurons has shown that ankyrin-G plays a key role in the regulation of GABAergic synapses on the axon initial segment and somatodendritic domain of pyramidal neurons where it interacts directly with the GABAA receptor associated protein (GABARAP) to stabilize cell surface GABAA receptors. Here, we generated a knock-in mouse model expressing a mutation that abolishes the ankyrin-G/GABARAP interaction (Ank3 W1989R) to understand how ankyrin-G and GABARAP regulate GABAergic circuitry in vivo. We found that Ank3 W1989R mice exhibit a striking reduction in forebrain GABAergic synapses resulting in pyramidal cell hyperexcitability and disruptions in network synchronization. In addition, we identified changes in pyramidal cell dendritic spines and axon initial segments consistent with compensation for hyperexcitability. Finally, we identified the ANK3 W1989R variant in a family with bipolar disorder, suggesting a potential role of this variant in disease. Our results highlight the importance of ankyrin-G in regulating forebrain circuitry and provide novel insights into how ANK3 loss-of-function variants may contribute to human disease.

scholarly journals The Drosophila melanogaster Toll Pathway Participates in Resistance to Infection by the Gram-Negative Human Pathogen Pseudomonas aeruginosa

2003 ◽  
Vol 71 (7) ◽  
pp. 4059-4066 ◽  
Author(s):  
Gee W. Lau ◽  
Boyan C. Goumnerov ◽  
Cynthia L. Walendziewicz ◽  
Jennifer Hewitson ◽  
Wenzhong Xiao ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Innate Immunity ◽  
Drosophila Melanogaster ◽  
Signaling Pathway ◽  
Virulence Factors ◽  
Loss Of Function ◽  
Gram Negative ◽  
Toll Signaling ◽  
Resistance To Infection

ABSTRACT Pseudomonas aeruginosa is a gram-negative pathogen that infects immunocompromised and cystic fibrosis patients. The molecular basis of the host-P. aeruginosa interaction and the effect of specific P. aeruginosa virulence factors on various components of the innate immunity pathways are largely unknown. We examine interactions between P. aeruginosa virulence factors and components of innate immunity response in the Drosophila melanogaster model system to reveal the importance of the Toll signaling pathway in resistance to infection by the P. aeruginosa human isolate PA14. Using the two PA14-isogenic mutants plcS and dsbA, we show that Drosophila loss-of-function mutants of Spatzle, the extracellular ligand of Toll, and Dorsal and Dif, two NF-κB-like transcription factors, allow increased P. aeruginosa infectivity within fly tissues. In contrast, a constitutively active Toll mutant and a loss-of-function mutant of Cactus, an IκB-like factor that inhibits the Toll signaling, reduce infectivity. Our finding that Dorsal activity is required to restrict P. aeruginosa infectivity in Drosophila provides direct in vivo evidence for Dorsal function in adult fly immunity. Additionally, our results provide the basis for future studies into interactions between P. aeruginosa virulence factors and components of the Toll signaling pathway, which is functionally conserved between flies and humans.

scholarly journals EHBP-1 Functions with RAB-10 during Endocytic Recycling in Caenorhabditis elegans

2010 ◽  
Vol 21 (16) ◽  
pp. 2930-2943 ◽  
Author(s):  
Anbing Shi ◽  
Carlos Chih-Hsiung Chen ◽  
Riju Banerjee ◽  
Doreen Glodowski ◽  
Anjon Audhya ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Mdck Cells ◽  
Cell Types ◽  
Loss Of Function ◽  
Endocytic Recycling ◽  
Intestinal Epithelia ◽  
Binding Partners ◽  
Cargo Transport ◽  
Two Hybrid

Caenorhabditis elegans RAB-10 functions in endocytic recycling in polarized cells, regulating basolateral cargo transport in the intestinal epithelia and postsynaptic cargo transport in interneurons. A similar role was found for mammalian Rab10 in MDCK cells, suggesting that a conserved mechanism regulates these related pathways in metazoans. In a yeast two-hybrid screen for binding partners of RAB-10 we identified EHBP-1, a calponin homology domain (CH) protein, whose mammalian homolog Ehbp1 was previously shown to function during endocytic transport of GLUT4 in adipocytes. In vivo we find that EHBP-1-GFP colocalizes with RFP-RAB-10 on endosomal structures of the intestine and interneurons and that ehbp-1 loss-of-function mutants share with rab-10 mutants specific endosome morphology and cargo localization defects. We also show that loss of EHBP-1 disrupts transport of membrane proteins to the plasma membrane of the nonpolarized germline cells, a defect that can be phenocopied by codepletion of RAB-10 and its closest paralog RAB-8. These results indicate that RAB-10 and EHBP-1 function together in many cell types and suggests that there are differences in the level of redundancy among Rab family members in polarized versus nonpolarized cells.

scholarly journals The Ig-like domain of Punctin/MADD-4 is the primary determinant for interaction with the ectodomain of neuroligin NLG-1

2020 ◽  
pp. jbc.RA120.014591
Author(s):  
Semeli Platsaki ◽  
Xin Zhou ◽  
Bérangère Pinan-Lucarré ◽  
Vincent Delauzun ◽  
Haijun Tu ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Matrix Protein ◽  
Neuromuscular Junctions ◽  
Heparan Sulphate ◽  
Extracellular Matrix Protein ◽  
Inhibitory Synapses ◽  
Primary Determinant ◽  
Gabaergic Synapses

Punctin/MADD-4, a member of the ADAMTSL extracellular matrix protein family, was identified as an anterograde synaptic organizer in the nematode Caenorhabditis elegans. At GABAergic neuromuscular junctions, the short isoform MADD-4B binds the ectodomain of neuroligin NLG-1, itself a postsynaptic organizer of inhibitory synapses. To identify the molecular bases of their partnership, we generated recombinant forms of the two proteins and carried out a comprehensive biochemical and biophysical study of their interaction, complemented by an in vivo localisation study. We show that spontaneous proteolysis of MADD-4B first generates a shorter N-MADD-4B form, which comprises four thrombospondin (TSP) and one Ig-like domains and binds NLG-1. A second processing event eliminates the C-terminal Ig-like domain along with the ability of N-MADD-4B to bind NLG-1. These data identify the Ig-like domain as the primary determinant for N-MADD-4B interaction with NLG-1 in vitro. We further demonstrate in vivo that this Ig-like domain is essential, albeit not sufficient per se, for efficient recruitment of GABAA receptors at GABAergic synapses in C. elegans. The interaction of N-MADD-4B with NLG-1 is also disrupted by heparin, used as a surrogate for the extracellular matrix component, heparan sulphate, and whose high-affinity binding to the Ig-like domain may proceed from surface charge complementarity, as suggested by homology 3D modelling. These data point to N-MADD-4B processing and cell-surface proteoglycan binding as two possible mechanisms that can regulate the interaction between MADD-4B and NLG-1 at GABAergic synapses.

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