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

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.

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

10.21203/rs.3.rs-100199/v1 ◽

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.

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

International Journal of Molecular Sciences ◽

10.3390/ijms22052645 ◽

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.

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Thymus leukemia antigen controls intraepithelial lymphocyte function and inflammatory bowel disease

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.0808242105 ◽

2008 ◽

Vol 105 (46) ◽

pp. 17931-17936 ◽

Cited By ~ 38

Author(s):

Danyvid Olivares-Villagómez ◽

Yanice V. Mendez-Fernandez ◽

Vrajesh V. Parekh ◽

Saif Lalani ◽

Tiffaney L. Vincent ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Intestinal Inflammation ◽

Genetic Model ◽

Critical Role ◽

Intraepithelial Lymphocytes ◽

Lymphocyte Function ◽

Intestinal Epithelial ◽

Inflammatory Bowel

Intestinal intraepithelial lymphocytes (IEL) bear a partially activated phenotype that permits them to rapidly respond to antigenic insults. However, this phenotype also implies that IEL must be highly controlled to prevent misdirected immune reactions. It has been suggested that IEL are regulated through the interaction of the CD8αα homodimer with the thymus leukemia (TL) antigen expressed by intestinal epithelial cells. We have generated and characterized mice genetically-deficient in TL expression. Our findings show that TL expression has a critical role in maintaining IEL effector functions. Also, TL deficiency accelerated colitis in a genetic model of inflammatory bowel disease. These findings reveal an important regulatory role of TL in controlling IEL function and intestinal inflammation.

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Myeloid-derived miR-223 regulates intestinal inflammation via repression of the NLRP3 inflammasome

Journal of Experimental Medicine ◽

10.1084/jem.20160462 ◽

2017 ◽

Vol 214 (6) ◽

pp. 1737-1752 ◽

Cited By ~ 139

Author(s):

Viola Neudecker ◽

Moritz Haneklaus ◽

Owen Jensen ◽

Ludmila Khailova ◽

Joanne C. Masterson ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Nlrp3 Inflammasome ◽

Untranslated Region ◽

Intestinal Inflammation ◽

Experimental Colitis ◽

Innate Immune ◽

Mouse Line ◽

Preclinical Models ◽

Inflammatory Monocytes ◽

Inflammatory Bowel

MicroRNA (miRNA)-mediated RNA interference regulates many immune processes, but how miRNA circuits orchestrate aberrant intestinal inflammation during inflammatory bowel disease (IBD) is poorly defined. Here, we report that miR-223 limits intestinal inflammation by constraining the nlrp3 inflammasome. miR-223 was increased in intestinal biopsies from patients with active IBD and in preclinical models of intestinal inflammation. miR-223-/y mice presented with exacerbated myeloid-driven experimental colitis with heightened clinical, histopathological, and cytokine readouts. Mechanistically, enhanced NLRP3 inflammasome expression with elevated IL-1β was a predominant feature during the initiation of colitis with miR-223 deficiency. Depletion of CCR2+ inflammatory monocytes and pharmacologic blockade of IL-1β or NLRP3 abrogated this phenotype. Generation of a novel mouse line, with deletion of the miR-223 binding site in the NLRP3 3′ untranslated region, phenocopied the characteristics of miR-223-/y mice. Finally, nanoparticle-mediated overexpression of miR-223 attenuated experimental colitis, NLRP3 levels, and IL-1β release. Collectively, our data reveal a previously unappreciated role for miR-223 in regulating the innate immune response during intestinal inflammation.

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ErbB-1 experssion in experimental model of inflammatory bowel disease in rats

Acta chirurgica iugoslavica ◽

10.2298/aci0402085t ◽

2004 ◽

Vol 51 (2) ◽

pp. 85-89 ◽

Cited By ~ 4

Author(s):

R. Trzcinski ◽

M. Bry ◽

W. Krajewska ◽

M. Kulig ◽

A. Dzyiki

Keyword(s):

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Intestinal Inflammation ◽

Growth Factor Receptor ◽

Experimental Colitis ◽

Altered Level ◽

Pcr Products ◽

Epidermal Growth ◽

Inflammatory Bowel ◽

Specific Symptoms

Background Ulcerative colitis (UC) and Crohn?s disease (CD) belong to inflammatory bowel disease (IBD). The etiology of IBD is still unknown. Therapy remains empiric or is used for the relief of specific symptoms. The erbB-1 oncogene coding epidermal growth factor receptor (EGFR) is typed as a prognostic marker in several benign and malignant tissues. The aim of our study was to examine the erbB-1 expression in experimental surgically performed model of IBD in rats and to find out if there is any correlation between severity of the intestinal inflammation and altered level of erbB-1 expression. After inducing an experimental colitis samples were taken from different parts of the intestine in all studied groups of rats for histopathology. ErbB-1 mRNA expression was estimated by RT-PCR. PCR products were separated on a 1,5% TBE-agarose gel and visualized with ethidium bromide. The integrated optical density (IOD) of electrophoretically separated amplification products was measured using a video densitometer and Gel-Pro 3.0 software. Nonparametrical statistical test has been used throughout in analyzing the results. Relative erbB-1 expression was determined by comparing to cyclophiline expression. Results Microscopic changes were similar to those observed in IBD. ErbB-1 expression was significantly higher in inflamed tissues of the bowel ( P=0.04 for the transverse colon and P=0.027 for the cecum). Significantly higher erbB-1 expression in inflamed tissues of the bowel suggests that EGFR overexpression may play a role in the pathogenesis of IBD. Overexpression of erbB-1 correlates with the severity of inflammation in bowel tissues.

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PPARγin Inflammatory Bowel Disease

PPAR Research ◽

10.1155/2012/620839 ◽

2012 ◽

Vol 2012 ◽

pp. 1-9 ◽

Cited By ~ 39

Author(s):

Vito Annese ◽

Francesca Rogai ◽

Alessia Settesoldi ◽

Siro Bagnoli

Keyword(s):

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Potential Role ◽

Intestinal Inflammation ◽

Experimental Colitis ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Beneficial Effects ◽

Inflammatory Bowel

Peroxisome proliferator-activated receptor gamma (PPARγ) is member of a family of nuclear receptors that interacts with nuclear proteins acting as coactivators and corepressors. The colon is a major tissue which expresses PPARγin epithelial cells and, to a lesser degree, in macrophages and lymphocytes and plays a role in the regulation of intestinal inflammation. Indeed, both natural and synthetic PPARγligands have beneficial effects in different models of experimental colitis, with possible implication in the therapy of inflammatory bowel disease (IBD). This paper will specifically focus on potential role of PPARγin the predisposition and physiopathology of IBD and will analyze its possible role in medical therapy.

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Neuroimmunomodulation in the Gut: Focus on Inflammatory Bowel Disease

Mediators of Inflammation ◽

10.1155/2016/1363818 ◽

2016 ◽

Vol 2016 ◽

pp. 1-14 ◽

Cited By ~ 10

Author(s):

Claudio Bernardazzi ◽

Beatriz Pêgo ◽

Heitor Siffert P. de Souza

Keyword(s):

Inflammatory Bowel Disease ◽

Nervous System ◽

Bowel Disease ◽

Intestinal Inflammation ◽

Critical Role ◽

Intestinal Immunity ◽

Intestinal Homeostasis ◽

Inflammatory Bowel ◽

Genetic And Environmental Factors ◽

External Stimuli

Intestinal immunity is finely regulated by several concomitant and overlapping mechanisms, in order to efficiently sense external stimuli and mount an adequate response of either tolerance or defense. In this context, a complex interplay between immune and nonimmune cells is responsible for the maintenance of normal homeostasis. However, in certain conditions, the disruption of such an intricate network may result in intestinal inflammation, including inflammatory bowel disease (IBD). IBD is believed to result from a combination of genetic and environmental factors acting in concert with an inappropriate immune response, which in turn interacts with nonimmune cells, including nervous system components. Currently, evidence shows that the interaction between the immune and the nervous system is bidirectional and plays a critical role in the regulation of intestinal inflammation. Recently, the maintenance of intestinal homeostasis has been shown to be under the reciprocal control of the microbiota by immune mechanisms, whereas intestinal microorganisms can modulate mucosal immunity. Therefore, in addition to presenting the mechanisms underlying the interaction between immune and nervous systems in the gut, here we discuss the role of the microbiota also in the regulation of neuroimmune crosstalk involved in intestinal homeostasis and inflammation, with potential implications to IBD pathogenesis.

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Brain-Gut Interactions in Inflammatory Bowel Disease: Mechanisms of Anorexia in Animal Models of Experimental Colitis

Canadian Journal of Gastroenterology ◽

10.1155/1996/863284 ◽

1996 ◽

Vol 10 (5) ◽

pp. 329-334

Author(s):

Harvey P Weingarten

Keyword(s):

Inflammatory Bowel Disease ◽

Central Nervous System ◽

Bowel Disease ◽

Cytokine Production ◽

Experimental Colitis ◽

Physiological Processes ◽

Disease Mechanisms ◽

The Central Nervous System ◽

Inflammatory Bowel ◽

The Brain

Physiological processes within the bowel are influenced constantly by signals from other organs, primarily the brain. The mechanisms by which inflammation of the gastrointestinal tract results in anorexia are unknown. Understanding how the inflammation-related signals in the periphery are communicated to the central nervous system and activate cytokine production in the brain remains an enormous challenge. Elucidation of these gut-brain communication mechanisms is essential to the development of appropriate and efficacious treatments for the eating and weight disturbances associated with inflammatory bowel disease.

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CCR8 Signaling via CCL1 Regulates Responses of Intestinal IFN-γ Producing Innate Lymphoid CelIs and Protects From Experimental Colitis

Frontiers in Immunology ◽

10.3389/fimmu.2020.609400 ◽

2021 ◽

Vol 11 ◽

Author(s):

Le Kang ◽

Angelika Schmalzl ◽

Tamara Leupold ◽

Miguel Gonzalez-Acera ◽

Raja Atreya ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Immune Cells ◽

Bowel Disease ◽

Immune Cell ◽

Intestinal Inflammation ◽

Experimental Colitis ◽

Lymphoid Cells ◽

Protective Function ◽

Inflammatory Bowel ◽

Ifn Γ

A diverse spectrum of immune cells populates the intestinal mucosa reflecting the continuous stimulation by luminal antigens. In lesions of patients with inflammatory bowel disease, an aberrant inflammatory process is characterized by a very prominent infiltrate of activated immune cells producing cytokines and chemokines. These mediators perpetuate intestinal inflammation or may contribute to mucosal protection depending on the cellular context. In order to further characterize this complex immune cell network in intestinal inflammation, we investigated the contribution of the chemokine receptor CCR8 to development of colitis using a mouse model of experimental inflammation. We found that CCR8−/− mice compared to wildtype controls developed strong weight loss accompanied by increased histological and endoscopic signs of mucosal damage. Further experiments revealed that this gut protective function of CCR8 seems to be selectively mediated by the chemotactic ligand CCL1, which was particularly produced by intestinal macrophages during colitis. Moreover, we newly identified CCR8 expression on a subgroup of intestinal innate lymphoid cells producing IFN-γ and linked a functional CCL1/CCR8 axis with their abundance in the gut. Our data therefore suggest that this pathway supports tissue-specific ILC functions important for intestinal homeostasis. Modulation of this regulatory circuit may represent a new strategy to treat inflammatory bowel disease in humans.

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Elevated Expression of AXL May Contribute to the Epithelial-to-Mesenchymal Transition in Inflammatory Bowel Disease Patients

Mediators of Inflammation ◽

10.1155/2018/3241406 ◽

2018 ◽

Vol 2018 ◽

pp. 1-11 ◽

Cited By ~ 3

Author(s):

Éva Boros ◽

Zoltán Kellermayer ◽

Péter Balogh ◽

Gerda Strifler ◽

Andrea Vörös ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Molecular Mechanisms ◽

Epithelial To Mesenchymal Transition ◽

Intestinal Inflammation ◽

Experimental Colitis ◽

Mesenchymal Transition ◽

Inflammatory Bowel ◽

Chronic Intestinal Inflammation

Understanding the molecular mechanisms inducing and regulating epithelial-to-mesenchymal transition (EMT) upon chronic intestinal inflammation is critical for understanding the exact pathomechanism of inflammatory bowel disease (IBD). The aim of this study was to determine the expression profile of TAM family receptors in an inflamed colon. For this, we used a rat model of experimental colitis and also collected samples from colons of IBD patients. Samples were taken from both inflamed and uninflamed regions of the same colon; the total RNA was isolated, and the mRNA and microRNA expressions were monitored. We have determined that AXL is highly induced in active-inflamed colon, which is accompanied with reduced expression of AXL-regulating microRNAs. In addition, the expression of genes responsible for inducing or maintaining mesenchymal phenotype, such as SNAI1, ZEB2, VIM, MMP9, and HIF1α, were all significantly induced in the active-inflamed colon of IBD patients while the epithelial marker E-cadherin (CDH1) was downregulated. We also show that, in vitro, monocytic and colonic epithelial cells increase the expression of AXL in response to LPS or TNFα stimuli, respectively. In summary, we identified several interacting genes and microRNAs with mutually exclusive expression pattern in active-inflamed colon of IBD patients. Our results shed light onto a possible AXL- and microRNA-mediated regulation influencing epithelial-to-mesenchymal transition in IBD.

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