scholarly journals Specific immune modulation of experimental colitis drives enteric alpha-synuclein accumulation and triggers age-related Parkinson-like brain pathology

2020 ◽  
Author(s):  
Stefan Grathwohl ◽  
Emmanuel Quansah ◽  
Nazia Maroof ◽  
Jennifer A Steiner ◽  
Liz Spycher ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Immune Modulation ◽  
Intestinal Inflammation ◽  
Critical Role ◽  
Experimental Colitis ◽  
Alpha Synuclein ◽  
Submucosal Plexus ◽  
Wild Type ◽  
Genetic Ablation ◽  
Dss Colitis

Abstract Background : Intraneuronal accumulation of a-synuclein (αSyn) is key in Parkinson’s disease (PD) pathogenesis. The pathogenic process is suggested to begin in the enteric nervous system decades before diagnosis of PD and then propagate into the brain. The triggers for these events are unclear but, in some patients, colitis might play a critical role. Methods : We administered lipopolysaccharide (LPS) or dextran sulfate sodium (DSS) to assess the effect of different types of experimental colitis on αSyn accumulation in the gut of αSyn transgenic and wild type mice and quantified local gene expression by RT-PCR and level of αSyn accumulation by immunofluorescence imaging. Immune modulation during the DSS colitis paradigm in the αSyn transgenic mice included genetic ablation of Cx3cr1 or treatment with recombinant IL-10. To determine long-term effects of experimental colitis, we induced DSS colitis in young αSyn transgenic mice and aged them under normal conditions up to nine or 21 months before analyzing their brains by immunohistochemistry. In vivo experiments were performed in randomized cohorts. Blinded experimenters performed image analysis and statistical analysis depended on data type (i.e., Student’s t-test, ANOVA, mixed-effects model). Results : We demonstrate that mild sustained or one strong insult of experimental DSS colitis triggers αSyn accumulation in the submucosal plexus of wild type and αSyn transgenic mice, while short-term mild DSS experimental colitis or inflammation induced by LPS does not have such an effect. Lack of macrophage-related Cx3cr1-signalling during DSS colitis increases accumulation of αSyn in the colonic submucosal plexus of αSyn transgenic mice while systemic treatment with immune-dampening IL-10 ameliorates this phenomenon. Additionally, DSS colitis-induced αSyn accumulation in young αSyn transgenic mice persists for months and is exacerbated by lack of Cx3cr1-signaling. Remarkably, experimental colitis at three months of age exacerbates the accumulation of aggregated phospho-Serine 129 αSyn in the midbrain (including the substantia nigra), in 21- but not 9-month-old αSyn transgenic mice. This increase in midbrain αSyn accumulation is accompanied by the loss of tyrosine hydroxylase-immunoreactive nigral neurons. Conclusions : Our data suggest that specific types of intestinal inflammation, mediated by monocyte/macrophage signaling, could play a critical role in the initiation and progression of PD.

scholarly journals Experimental colitis drives enteric alpha-synuclein accumulation and Parkinson-like brain pathology

2018 ◽  
Author(s):  
Stefan Grathwohl ◽  
Emmanuel Quansah ◽  
Nazia Maroof ◽  
Jennifer A. Steiner ◽  
Liz Spycher ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Transgenic Mice ◽  
Intestinal Inflammation ◽  
Critical Role ◽  
Experimental Colitis ◽  
Alpha Synuclein ◽  
Brain Pathology ◽  
Inflammatory Bowel ◽  
Immune Pathways ◽  
The Brain

AbstractIntraneuronal accumulation of α-synuclein (αSyn) is key in the pathogenesis of Parkinson’s disease (PD). Published studies suggest that this process begins in the enteric nervous system (ENS) and propagates into the brain decades before clinical diagnosis of PD. The triggers and mechanisms underlying the accumulation of αSyn remain unknown but evidence is growing, that immune pathways and in particular colitis may play a critical role. Here we demonstrate that patients with inflammatory bowel disease (IBD) exhibit αSyn accumulation in their colon. We then confirmed in an experimental model of IBD that intestinal inflammation can trigger αSyn accumulation in the ENS of wildtype and αSyn transgenic mice. We discovered that the type and degree of inflammation modulates the extent of αSyn accumulation in the colon and that macrophage-related signaling limits this process. Remarkably, experimental colitis at three months of age exacerbated the accumulation of aggregated phospho-Serine 129 αSyn in the midbrain, including the substantia nigra, in 21-month but not 9-month-old αSyn transgenic mice. This was accompanied by loss of nigral tyrosine hydroxylase-immunoreactive neurons, another neuropathological hallmark of PD. Together, our data suggest a critical role for intestinal inflammation in the initiation and progression of PD.

scholarly journals Hyaluronan Synthase 3 Null Mice Exhibit Decreased Intestinal Inflammation and Tissue Damage in the DSS-Induced Colitis Model

2015 ◽  
Vol 2015 ◽  
pp. 1-13 ◽  
Author(s):  
Sean P. Kessler ◽  
Dana R. Obery ◽  
Carol de la Motte
Keyword(s):  
Intestinal Inflammation ◽  
Inflammatory Diseases ◽  
Experimental Colitis ◽  
Hyaluronan Synthase ◽  
Wild Type ◽  
Colon Tissue ◽  
Dss Colitis ◽  
Chemically Induced ◽  
Inflammatory Bowel ◽  
Colitis Model

Hyaluronan (HA) overproduction is a hallmark of multiple inflammatory diseases, including inflammatory bowel disease (IBD). Hyaluronan can act as a leukocyte recruitment molecule and in the most common mouse model of intestinal inflammation, the chemically induced dextran sodium sulfate (DSS) experimental colitis model, we previously determined that changes in colon distribution of HA occur before inflammation. Therefore, we hypothesized that, during a pathologic challenge, HA promotes inflammation. In this study, we tested the progression of inflammation in mice null for the hyaluronan synthase genes (HAS1, HAS3, or both HAS1 and HAS3) in the DSS-colitis model. Our data demonstrate that both the HAS1/HAS3 double and the HAS3 null mice are protected from colitis, compared to wild-type and HAS1 null mice, as determined by measurement of weight loss, disease activity, serum IL-6 levels, histologic scoring, and immunohistochemistry. Most notable is the dramatic increase in submucosal microvasculature, hyaluronan deposition, and leukocyte infiltration in the inflamed colon tissue of wild-type and HAS1 null mice. Our data suggest, HAS3 plays a crucial role in driving gut inflammation. Developing a temporary targeted therapeutic intervention of HAS3 expression or function in the microcirculation may emerge as a desirable strategy toward tempering colitis in patients undergoing flares of IBD.

scholarly journals Loss of Nckx3 Exacerbates Experimental DSS-Induced Colitis in Mice through p53/NF-κB Pathway

2021 ◽  
Vol 22 (5) ◽  
pp. 2645
Author(s):  
Dinh Nam Tran ◽  
Seon Myeong Go ◽  
Seon-Mi Park ◽  
Eui-Man Jung ◽  
Eui-Bae Jeung
Keyword(s):  
Immune Response ◽  
Cellular Proliferation ◽  
Intestinal Inflammation ◽  
Critical Role ◽  
Experimental Colitis ◽  
Innate Immune ◽  
Inflammatory Conditions ◽  
Bowel Diseases ◽  
Inflammatory Bowel ◽  
Microarray Analyses

Inflammatory bowel diseases (IBDs) comprises a range of chronic inflammatory conditions of the intestinal tract. The incidence and prevalence of IBDs are increasing worldwide, but the precise etiology of these diseases is not completely understood. Calcium signaling plays a regulatory role in cellular proliferation. Nckx3, a potassium-dependent Na+/Ca2+ exchanger, is not only expressed in the brain but also in the aortic, uterine, and intestinal tissues, which contain abundant smooth muscle cells. This study investigated the role of Nckx3 in intestinal inflammation. Microarray analyses revealed the upregulation of the innate immune response-associated genes in the duodenum of Nckx3 knockout (KO) mice. The Nckx3 KO mice also showed an increase in IBD- and tumorigenesis-related genes. Using dextran sodium sulfate (DSS)-induced experimental colitis mice models, the Nckx3 KO mice showed severe colitis. Furthermore, the pathways involving p53 and NF-κB signaling were significantly upregulated by the absence of Nckx3. Overall, Nckx3 plays a critical role in the innate immune and immune response and may be central to the pathogenesis of IBD.

Adenoviral E3-14.7K protein in LPS-induced lung inflammation

2000 ◽  
Vol 278 (4) ◽  
pp. L631-L639 ◽  
Author(s):  
Kevin S. Harrod ◽  
Amber D. Mounday ◽  
Jeffrey A. Whitsett
Keyword(s):  
Transgenic Mice ◽  
Lung Inflammation ◽  
Cell Injury ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Respiratory Epithelium ◽  
Wild Type ◽  
Intracellular Staining ◽  
Intratracheal Administration ◽  
Tnf Α

The adenoviral E3-14.7K protein is a cytoplasmic protein synthesized after adenoviral infection. To assess the contribution of E3-14.7K-sensitive pathways in the modulation of inflammation by the respiratory epithelium, inflammatory responses to intratracheal lipopolysaccharide (LPS) and tumor necrosis factor (TNF)-α were assessed in transgenic mice bearing the adenoviral E3-14.7K gene under the direction of the surfactant protein (SP) C promoter. When E3-14.7K transgenic mice were administered LPS intratracheally, lung inflammation as indicated by macrophage and neutrophil accumulation in bronchoalveolar lavage fluid was decreased compared with wild-type control mice. Lung inflammation and epithelial cell injury were decreased in E3-14.7K mice 24 and 48 h after LPS administration. Intracellular staining for surfactant proprotein (proSP) B, proSP-C, and SP-B was decreased and extracellular staining was markedly increased in wild-type mice after LPS administration, consistent with LPS-induced lung injury. In contrast, intense intracellular staining of proSP-B, proSP-C, and SP-B persisted in type II cells of E3-14.7K mice, whereas extracellular staining of proSP-B and proSP-C was absent. Inhibitory effects of intratracheal LPS on SP-C mRNA were ameliorated by expression of the E3-14.7Kgene. Similar to the response to LPS, lung inflammation after intratracheal administration of TNF-α was decreased in E3-14.7K transgenic mice. Levels of TNF-α after LPS administration were similar in wild-type and E3-14.7K-bearing mice. Cell-selective expression of E3-14.7K in the respiratory epithelium inhibited LPS- and TNF-α-mediated lung inflammation, demonstrating the critical role of respiratory epithelial cells in LPS- and TNF-α-induced lung inflammation.

scholarly journals Lactobacillus paracaseiReduces Intestinal Inflammation in Adoptive Transfer Mouse Model of Experimental Colitis

2011 ◽  
Vol 2011 ◽  
pp. 1-13 ◽  
Author(s):  
Manuel Oliveira ◽  
Nabil Bosco ◽  
Genevieve Perruisseau ◽  
Jeanne Nicolas ◽  
Iris Segura-Roggero ◽  
...  
Keyword(s):  
Mouse Model ◽  
Adoptive Transfer ◽  
Immune Modulation ◽  
Intestinal Inflammation ◽  
Experimental Colitis ◽  
Neutrophil Infiltration ◽  
Lactobacillus Paracasei ◽  
Therapeutic Benefits

Studies showed that specific probiotics provide therapeutic benefits in inflammatory bowel disease.In vitroevidence suggested thatLactobacillus paracaseialso called ST11 (CNCM I-2116) is a potent strain with immune modulation properties. However, little is known about its capacity to alleviate inflammatory symptomsin vivoIn this context, the main objective of this study was to investigate the role of ST11 on intestinal inflammation using the adoptive transfer mouse model of experimental colitis. Rag2-/-recipient mice were fed with ST11 (109CFU/day)a month prior toinduce colitis by adoptive transfer of naive T cells. One month later, in clear contrast to nonfed mice, weight loss was significantly reduced by 50% in ST11-fed mice. Further analysis of colon specimens revealed a significant reduction neutrophil infiltration and mucosal expression of IL1β, IL-6, and IL12 proinflammatory cytokines, whereas no consistent differences in expression of antibacterial peptides or tight junction proteins were observed between PBS and ST11-fed mice. All together, our results demonstrate that oral administration of ST11 was safe and had a significant preventive effect on colitis. We conclude that probiotics such asLactobacillus paracaseiharbor worthwhilein vivoimmunomodulatory properties to prevent intestinal inflammation by nutritional approaches.

scholarly journals Reduced oxidative and nitrosative damage in murine experimental colitis in the absence of inducible nitric oxide synthase

Gut ◽  
1999 ◽  
Vol 45 (2) ◽  
pp. 199-209 ◽  
Author(s):  
B Zingarelli ◽  
C Szabó ◽  
A L Salzman
Keyword(s):  
Nitric Oxide ◽  
Nitrosative Stress ◽  
Experimental Colitis ◽  
Neutrophil Infiltration ◽  
Intercellular Adhesion Molecule ◽  
Myeloperoxidase Activity ◽  
Wild Type ◽  
Oxidative And Nitrosative Stress ◽  
Intense Staining ◽  
Genetic Ablation

BACKGROUNDOxidative and nitrosative stress have been implicated in the pathogenesis of inflammatory bowel diseases.AIMSTo study the role of nitric oxide (NO) derived from inducible NO synthase (iNOS) in an experimental model of murine enterocolitis.METHODSTrinitrobenzene sulphonic acid (TNBS) was instilled per rectum to induce a lethal colitis in iNOS deficient mice and in wild type controls. The distal colon was evaluated for histological evidence of inflammation, iNOS expression and activity, tyrosine nitration and malondialdehyde formation (as indexes of nitrosative and oxidative stress), myeloperoxidase activity (as index of neutrophil infiltration), and tissue localisation of intercellular adhesion molecule 1 (ICAM-1).RESULTSTNBS administration induced a high mortality and weight loss associated with a severe colonic mucosal erosion and ulceration, increased myeloperoxidase activity, increased concentrations of malondialdehyde, and an intense staining for nitrotyrosine and ICAM-1 in wild type mice. Genetic ablation of iNOS gene conferred to mice a significant resistance to TNBS induced lethality and colonic damage, and notably reduced nitrotyrosine formation and concentrations of malondialdehyde; it did not, however, affect neutrophil infiltration and intestinal ICAM-1 expression in the injured tissue.CONCLUSIONData show that activation of iNOS is required for nitrosative and oxidative damage in experimental colitis.

scholarly journals Enhanced Susceptibility of Galectin-1 Deficient Mice to Experimental Colitis

2021 ◽  
Vol 12 ◽  
Author(s):  
Raquel Fernandez-Perez ◽  
Mercedes Lopez-Santalla ◽  
Rebeca Sánchez-Domínguez ◽  
Omaira Alberquilla ◽  
Irene Gutiérrez-Cañas ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Inflammatory Response ◽  
Intestinal Inflammation ◽  
Experimental Colitis ◽  
Cell Trafficking ◽  
Wild Type ◽  
Cell Reactivity ◽  
Deficient Mice

Galectin-1 is a β-galactoside-binding lectin, ubiquitously expressed in stromal, epithelial, and different subsets of immune cells. Galectin-1 is the prototype member of the galectin family which shares specificity with β-galactoside containing proteins and lipids. Immunomodulatory functions have been ascribed to endogenous galectin-1 due to its induction of T cell apoptosis, inhibitory effects of neutrophils and T cell trafficking. Several studies have demonstrated that administration of recombinant galectin-1 suppressed experimental colitis by modulating adaptive immune responses altering the fate and phenotype of T cells. However, the role of endogenous galectin-1 in intestinal inflammation is poorly defined. In the present study, the well-characterized acute dextran sulfate sodium (DSS)-induced model of ulcerative colitis was used to study the function of endogenous galectin-1 during the development of intestinal inflammation. We found that galectin-1 deficient mice (Lgals1−/− mice) displayed a more severe intestinal inflammation, characterized by significantly elevated clinical scores, than their wild type counterparts. The mechanisms underlying the enhanced inflammatory response in colitic Lgals1−/− mice involved an altered Th17/Th1 profile of effector CD4+ T cells. Furthermore, increased frequencies of Foxp3+CD4+ regulatory T cells in colon lamina propria in Lgals1−/− mice were found. Strikingly, the exacerbated intestinal inflammatory response observed in Lgals1−/− mice was alleviated by adoptive transfer of wild type Foxp3+CD4+ regulatory T cells at induction of colitis. Altogether, these data highlight the importance of endogenous galectin-1 as a novel determinant in regulating T cell reactivity during the development of intestinal inflammation.

scholarly journals Deciphering the combinatorial influence of diet and the microbiota on experimental colitis

2017 ◽  
Author(s):  
Sean R. Llewellyn ◽  
Graham J. Britton ◽  
Eduardo J. Contijoch ◽  
Arthur Mortha ◽  
Jean-Frederic Colombel ◽  
...  
Keyword(s):  
Dietary Protein ◽  
Intestinal Inflammation ◽  
High Protein Diet ◽  
Experimental Colitis ◽  
Mucosal Inflammation ◽  
Germ Free ◽  
Dss Colitis ◽  
Microbial Density ◽  
Specific Pathogen ◽  
Host Physiology

AbstractBackground & AimsThe complex interactions between diet and the microbiota that influence mucosal inflammation and inflammatory bowel disease are poorly understood. Experimental colitis models provide the opportunity to control and systematically perturb diet and the microbiota in parallel to quantify the contributions between multiple dietary ingredients and the microbiota on host physiology and colitis.MethodsTo examine the interplay of diet and the gut microbiota on host health and colitis, we fed over 40 different diets with varied macronutrient sources and concentrations to specific pathogen free or germ free mice either in the context of healthy, unchallenged animals or colitis models (dextran sodium sulfate (DSS) and T cell transfer).ResultsDiet influenced physiology in both health and colitis across all models, with the concentration of protein and psyllium fiber having the most profound effects. Increasing dietary protein elevated gut microbial density and worsened DSS colitis severity. Depleting gut microbial density by using germ-free animals or antibiotics negated the effect of a high protein diet. Psyllium fiber influenced host physiology and attenuated colitis severity through microbiota-dependent and microbiota-independent mechanisms. Combinatorial perturbations to dietary protein and psyllium fiber in parallel explain most variation in gut microbial density, intestinal permeability, and DSS colitis severity, and changes in one ingredient can be offset by changes in the other.ConclusionsOur results demonstrate the importance of examining complex mixtures of nutrients to understand the role of diet in intestinal inflammation.

Abstract 384: Interleukin-6 Mediates the Altered Platelet Function Associated with Experimental Colonic Inflammation

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Li-Sue S Yan
Keyword(s):  
Platelet Activation ◽  
Platelet Function ◽  
Interleukin 6 ◽  
Blood Platelets ◽  
Critical Role ◽  
Experimental Colitis ◽  
Membrane Expression ◽  
Colonic Inflammation ◽  
Dss Colitis ◽  
Chronic Infusion

Patients with inflammatory bowel disease (IBD) are susceptible to microvascular thrombosis and thromboembolism. The increased incidence of thrombosis is accompanied by enhanced coagulation and abnormalities in platelet function. Clinical studies have also revealed alterations in platelet activation, enhanced platelet-leukocyte interaction, and elevated plasma levels of prothrombotic cytokines, such as IL-6. This study was directed towards determining whether: 1) experimental colitis, induced by 6 days of dextran sodium sulfate (DSS) ingestion, is associated with platelet activation and the formation of platelet-leukocyte aggregates (PLAs), 2) IL-6 deficiency alters these responses to DSS colitis, and 3) the platelet abnormalities observed in DSS mice can be recapitulated by chronic infusion of murine recombinant IL-6. Flow cytometry was used to characterize platelet function in heparin-anticoagulated whole blood. Platelets were identified by characteristic light scattering and membrane expression of CD41. Platelet activation was monitored using the expression of an activation epitope of GPIIb/IIIa integrin (with JON/A antibody). The combination of CD41, CD45.2, Gr-1, F4/80 and isotype control antibodies were used to detect and quantify aggregates of leukocytes, neutrophils and monocytes with platelets in control, wild type (WT) colitic, IL-6 -/- colitic, and WT mice implanted with IL-6 loaded Alzet osmotic minipumps (for 6 days). Our results indicate that DSS colitis is associated with increased numbers of activated platelets and the formation of aggregates of leukocytes (PLA), neutrophils (PNA) and monocytes (PMA) with platelets. These platelet responses to experimental colitis were largely undetected in IL-6 -/- mice. Chronic infusion (at a rate that yielded plasma IL-6 levels similar to those detected in DSS colitic mice) of IL-6 recapitulated the increased platelet activation and formation of PLA, PNA, and PMA observed in DSS-colitic mice. Collectively, these findings show that the altered platelet function detected in human IBD can be reproduced in an animal model of colonic inflammation and that interleukin-6 plays a critical role in the genesis of these platelet abnormalities in the setting of experimental IBD.

scholarly journals Abrogation of Experimental Colitis Correlates with Increased Apoptosis in Mice Deficient for Cd44 Variant Exon 7 (Cd44v7)

2000 ◽  
Vol 191 (12) ◽  
pp. 2053-2064 ◽  
Author(s):  
Bianca M. Wittig ◽  
Britt Johansson ◽  
Margot Zöller ◽  
Christoph Schwärzler ◽  
Ursula Günthert
Keyword(s):  
Mononuclear Cells ◽  
Intestinal Inflammation ◽  
Experimental Colitis ◽  
Trinitrobenzene Sulfonic Acid ◽  
Wild Type ◽  
Cd40 Ligation ◽  
Th Cells ◽  
Variant Exon ◽  
Cd44 Variant ◽  
Deficient Mice

Experimental colitis in mice is characterized by infiltration of activated T helper (Th) cells and macrophages into the lamina propria. Particularly, these cells expressed CD44 variant exon 7 (CD44v7)-containing isoforms. Upregulation of CD44v7 isoforms was induced by CD40 ligation, an inflammation-driving interaction between activated Th cells and macrophages. To define the role of CD44v7 in colitis, mice bearing a targeted deletion for exon v7 were generated. In trinitrobenzene sulfonic acid–induced colitis, wild-type mice developed severe signs of persistent inflammation. Mice lacking CD44v7 initially showed unspecific inflammation, then recovered completely. The pathogenic origin was shown to reside in bone marrow–derived CD44v7+ cells, because adoptive transfer experiments demonstrated an absolute requirement for CD44v7 on hematopoietic cells for maintenance of colitis. Interleukin (IL)-10–deficient mice, which develop a chronic Th1-driven enterocolitis, were crossbred with CD44v6/v7 null mice. In IL-10 × CD44v6/v7 double deficient mice, intestinal inflammation developed only weakly and at an older age. Analysis of cell death in the inflamed lesions revealed that mononuclear cells in the CD44v7 null infiltrates had higher rates of apoptosis than those from wild-type mice. Thus, the region encoded by CD44v7 appears to be essential for survival of effector lymphocytes, resulting in persistence of inflammation.

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