scholarly journals P093 Crosstalk between Toll-like receptor 4 and enteric serotonergic pathways in a mouse model of dinitrobenzene sulfonic acid-induced colitis

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S182-S182
Author(s):  
S Cerantola ◽  
M Ridolfi ◽  
S Faggin ◽  
M Tegon ◽  
G Bussolaro ◽  
...  
Keyword(s):  
Small Intestine ◽  
Mouse Model ◽  
Sulfonic Acid ◽  
Activity Index ◽  
Muscle Tension ◽  
Disease Activity Index ◽  
Fold Increase ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Potential Benefits

Abstract Background Changes in serotonin (5-HT) levels, anomalies in serotonergic and cholinergic machinery and altered Toll-like receptor 4 (TLR4) expression have been shown in IBD in patients and related animal models. Thus, we aimed to assess the crosstalk of enteric serotonergic system and TLR4 signalling in a mouse model of dinitrobenzene sulfonic acid (DNBS)-induced colitis. Methods Male C57/Bl6 (WT) and TLR4−/− mice (9 ± 2 weeks old; N = 10 mice) were presensitised with 1% dinitrobenzene sulfonic acid (DNBS), and after 1 week was intrarectally instilled with 2.5% DNBS. Small intestine inflammation was measured by disease activity index and histological analysis. Changes in ileal muscle tension were isometrically recorded following: (1) cumulative addition of carbachol (CCh; 0.1–100 µM); (2) electric field stimulation (EFS, 0–40 Hz); (3) 60 mM KCl; (4) 30 μM 5-HT addition with or without 0.1 μM ondansetron (5-HT3R antagonist). Immunofluorescence distribution of the neuronal HuC/D and nNOS and glial GFAP markers were determined in longitudinal-muscle-myenteric plexus whole mounts (LMMPs) by confocal microscopy. Results In WT mice, DNBS treatment altered receptor and not-receptor mediated responses (+120% of Emax to CCh and +103% of contraction to KCl, respectively; p < 0.001, N = 5 mice/group) together with an altered cholinergic neurotransmission (−50% at 10 Hz; p < 0.01, N = 5 mice/group) and 2-fold increase to 30 μM 5-HT-mediated response (p < 0.001, N = 5 mice/group). After DNBS treatment TLR4−/− mice showed a significant increase in excitatory-mediated response (+98% of Emax to CCh; +80% of contraction to KCl; +120% at 10 Hz; p < 0.001, N = 5 mice/group) together with a significant reduction of 30 μM 5-HT-mediated response (−50%, p < 0.001, N = 5 mice/group). These changes were associated to a significant decrease of the total number of HuC/D+ neurons (−44% and −19% for WT DNBS and TLR4 DNBS mice, respectively) together with a 1.3-fold increase in S100b immunofluorescence in WT mice after DNBS treatment. Conclusion These findings not only suggest an important role of TLR4 in small intestine neuromuscular dysfunction during colitis but also provide novel information on the potential benefits of targeting TLR4 in various gut disorders that exhibit aberrant cholinergic and 5-HT signalling.

scholarly journals CD4+CD25+Foxp3+ regulatory T cells regulate immune balance in unexplained recurrent spontaneous abortion via the Toll-like receptor 4/nuclear factor-κB pathway

2020 ◽  
Vol 48 (12) ◽  
pp. 030006052098094
Author(s):  
Shuang Qin ◽  
Li Li ◽  
Jia Liu ◽  
Jinrui Zhang ◽  
Qing Xiao ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Inflammatory Response ◽  
Mouse Model ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Unexplained Recurrent Spontaneous Abortion ◽  
Tlr4 Antagonist

Objective The present study aimed to evaluate the effects of cluster of differentiation (CD)4+CD25+ forkhead box p3 (Foxp3)+ regulatory T cells (Tregs) on unexplained recurrent spontaneous abortion (URSA) and the associated mechanisms. Methods The proportion of CD4+CD25+Foxp3+ Tregs and inflammatory cytokine concentrations in the peripheral blood of women with URSA were measured by flow cytometry and enzyme-linked immunosorbent assay, respectively. CBA/JxDBA/2J mating was used to establish an abortion-prone mouse model and the model mice were treated with the Toll-like receptor 4 (TLR4) antagonist E5564 and the TLR4 agonist lipopolysaccharide. Results The proportion of CD4+CD25+Foxp3+ Tregs was decreased and the inflammatory response was increased in women with URSA. In the abortion-prone mouse model, E5564 significantly increased the proportion of CD4+CD25+Foxp3+ Tregs, decreased the inflammatory response, and increased Foxp3 mRNA and protein expression. Lipopolysaccharide had adverse effects on the abortion-prone model. Conclusions These data suggest that CD4+CD25+Foxp3+ Tregs regulate immune homeostasis in URSA via the TLR4/nuclear factor-κB pathway, and that the TLR4 antagonist E5564 may be a novel and potential drug for treating URSA.

scholarly journals Neuroprotective Effects of Toll-Like Receptor 4 Antagonism in Spinal Cord Cultures and in a Mouse Model of Motor Neuron Degeneration

2012 ◽  
Vol 18 (6) ◽  
pp. 971-981 ◽  
Author(s):  
Massimiliano De Paola ◽  
Alessandro Mariani ◽  
Paolo Bigini ◽  
Marco Peviani ◽  
Giovanni Ferrara ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Mouse Model ◽  
Motor Neuron ◽  
Toll Like Receptor ◽  
Motor Neuron Degeneration ◽  
Toll Like Receptor 4 ◽  
Neuron Degeneration ◽  
Neuroprotective Effects

Implications for trefoil factor 2 and toll-like receptor 4 involvement in a mouse model of Necrotizing Enterocolitis

2005 ◽  
Vol 201 (3) ◽  
pp. S53
Author(s):  
Cynthia A. Gingalewski ◽  
Robert Finberg ◽  
Rhonda Yantiss ◽  
Robert Kiley ◽  
Evelyn Kurt-Jones
Keyword(s):  
Mouse Model ◽  
Necrotizing Enterocolitis ◽  
Toll Like Receptor ◽  
Trefoil Factor ◽  
Toll Like Receptor 4 ◽  
Trefoil Factor 2

scholarly journals Toll‐Like Receptor 4 Is Not Involved in Host Defense against PulmonaryLegionella pneumophilaInfection in a Mouse Model

2002 ◽  
Vol 186 (4) ◽  
pp. 570-573 ◽  
Author(s):  
Kamilla D. Lettinga ◽  
Sandrine Florquin ◽  
Peter Speelman ◽  
Ruud van Ketel ◽  
Tom van der Poll ◽  
...  
Keyword(s):  
Mouse Model ◽  
Host Defense ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4

scholarly journals Toll-like receptor 4-dependent Kupffer cell activation and liver injury in a novel mouse model of parenteral nutrition and intestinal injury

Hepatology ◽  
2012 ◽  
Vol 55 (5) ◽  
pp. 1518-1528 ◽  
Author(s):  
Karim C. El Kasmi ◽  
Aimee L. Anderson ◽  
Michael W. Devereaux ◽  
Sophie A. Fillon ◽  
J. Kirk Harris ◽  
...  
Keyword(s):  
Liver Injury ◽  
Mouse Model ◽  
Parenteral Nutrition ◽  
Kupffer Cell ◽  
Cell Activation ◽  
Intestinal Injury ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4

scholarly journals Therapeutic Potential of Anti-Interferon α Vaccination on SjS-Related Features in the MRL/lpr Autoimmune Mouse Model

2021 ◽  
Vol 12 ◽  
Author(s):  
Martin Killian ◽  
Fabien Colaone ◽  
Philippe Haumont ◽  
Carole Nicco ◽  
Olivier Cerles ◽  
...  
Keyword(s):  
Mouse Model ◽  
Disease Activity ◽  
Sjögren’S Syndrome ◽  
Sjögren's Syndrome ◽  
Activity Index ◽  
Vaccination Strategy ◽  
Disease Activity Index ◽  
Sjogren’S Syndrome ◽  
Sjogren's Syndrome ◽  
Sjögren‘S Syndrome

Sjögren’s syndrome (SjS) is a frequent systemic autoimmune disease responsible for a major decrease in patients’ quality of life, potentially leading to life-threatening conditions while facing an unmet therapeutic need. Hence, we assessed the immunogenicity, efficacy, and tolerance of IFN-Kinoid (IFN-K), an anti-IFNα vaccination strategy, in a well-known mouse model of systemic autoimmunity with SjS-like features: MRL/MpJ-Faslpr/lpr (MRL/lpr) mice. Two cohorts (with ISA51 or SWE01 as adjuvants) of 26 female MRL/lpr were divided in parallel groups, “controls” (not treated, PBS and Keyhole Limpet Hemocyanin [KLH] groups) or “IFN-K” and followed up for 122 days. Eight-week-old mice received intra-muscular injections (days 0, 7, 28, 56 and 84) of PBS, KLH or IFN-K, emulsified in the appropriate adjuvant, and blood samples were serially collected. At sacrifice, surviving mice were euthanized and their organs were harvested for histopathological analysis (focus score in salivary/lacrimal glands) and IFN signature evaluation. SjS-like features were monitored. IFN-K induced a disease-modifying polyclonal anti-IFNα antibody response in all treated mice with high IFNα neutralization capacities, type 1 IFN signature’s reduction and disease features’ (ocular and oral sicca syndrome, neuropathy, focus score, glandular production of BAFF) improvement, as reflected by the decrease in Murine Sjögren’s Syndrome Disease Activity Index (MuSSDAI) modelled on EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI). No adverse effects were observed. We herein report on the strong efficacy of an innovative anti-IFNα vaccination strategy in a mouse model of SjS, paving the way for further clinical development (a phase IIb trial has just been completed in systemic lupus erythematosus with promising results).

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