scholarly journals The oxysterol synthesizing enzyme CH25H contributes to the development of intestinal fibrosis

2018 ◽  
Author(s):  
T. Raselli ◽  
A. Wyss ◽  
M.N. Gonzalez Alvarado ◽  
B. Weder ◽  
C. Mamie ◽  
...  
Keyword(s):  
Immune Responses ◽  
Dextran Sulfate ◽  
Biological Processes ◽  
Intestinal Fibrosis ◽  
Oxidized Cholesterol ◽  
Sodium Dextran Sulfate ◽  
Transplant Model ◽  
And Oxidative Stress ◽  
Colitis Model ◽  
Transplantation Model

AbstractIntestinal fibrosis and stenosis are common complications of Crohn’s disease (CD), frequently requiring surgery. Anti-inflammatory strategies can only partially prevent fibrosis; hence, anti-fibrotic therapies remain an unmet clinical need. Oxysterols are oxidized cholesterol derivatives, with important roles in various biological processes. The enzyme cholesterol 25-hydroxylase (CH25H) converts cholesterol to 25-hydroxycholesterol (25-HC), which modulates immune responses and oxidative stress. In human intestinal samples from CD patients we found a strong correlation of CH25H mRNA expression with the expression of fibrosis markers. We demonstrate reduced intestinal fibrosis in mice deficient for the CH25H enzyme using the sodium dextran sulfate (DSS)-induced chronic colitis model. Additionally, using a heterotopic transplantation model of intestinal fibrosis, we demonstrate reduced collagen deposition and lower concentrations of hydroxyproline in CH25H knockouts. In the heterotopic transplant model, CH25H was expressed in fibroblasts. Taken together, our findings indicate an involvement of oxysterol synthesis in the pathogenesis of intestinal fibrosis.

scholarly journals The Oxysterol Synthesising Enzyme CH25H Contributes to the Development of Intestinal Fibrosis

2019 ◽  
Vol 13 (9) ◽  
pp. 1186-1200 ◽  
Author(s):  
T Raselli ◽  
A Wyss ◽  
M N Gonzalez Alvarado ◽  
B Weder ◽  
C Mamie ◽  
...  
Keyword(s):  
Immune Responses ◽  
Biological Processes ◽  
Heterotopic Transplantation ◽  
Dextran Sulphate ◽  
Chronic Colitis ◽  
Intestinal Fibrosis ◽  
Transplant Model ◽  
And Oxidative Stress ◽  
Colitis Model ◽  
Transplantation Model

Abstract Intestinal fibrosis and stenosis are common complications of Crohn’s disease [CD], frequently requiring surgery. Anti-inflammatory strategies can only partially prevent fibrosis; hence, anti-fibrotic therapies remain an unmet clinical need. Oxysterols are oxidised cholesterol derivatives with important roles in various biological processes. The enzyme cholesterol 25-hydroxylase [CH25H] converts cholesterol to 25-hydroxycholesterol [25-HC], which modulates immune responses and oxidative stress. In human intestinal samples from CD patients, we found a strong correlation of CH25H mRNA expression with the expression of fibrosis markers. We demonstrate reduced intestinal fibrosis in mice deficient for the CH25H enzyme, using the sodium dextran sulphate [DSS]-induced chronic colitis model. Additionally, using a heterotopic transplantation model of intestinal fibrosis, we demonstrate reduced collagen deposition and lower concentrations of hydroxyproline in CH25H knockouts. In the heterotopic transplant model, CH25H was expressed in fibroblasts. Taken together, our findings indicate an involvement of oxysterol synthesis in the pathogenesis of intestinal fibrosis.

scholarly journals Intestinal mesenchymal cells regulate immune responses and promote epithelial regeneration in vitro and in dextran sulfate sodium‐induced experimental colitis in mice

2021 ◽  
Author(s):  
Laura Hidalgo‐Garcia ◽  
José Alberto Molina‐Tijeras ◽  
Francisco Huertas‐Peña ◽  
Antonio Jesús Ruiz‐Malagón ◽  
Patricia Diez‐Echave ◽  
...  
Keyword(s):  
Immune Responses ◽  
Dextran Sulfate ◽  
Dextran Sulfate Sodium ◽  
Experimental Colitis ◽  
Mesenchymal Cells ◽  
Epithelial Regeneration ◽  
Regeneration In Vitro

scholarly journals Acetylcholine-producing T cells augment innate immune-driven colitis but are redundant in T cell-driven colitis

2019 ◽  
Vol 317 (5) ◽  
pp. G557-G568 ◽  
Author(s):  
Rose A. Willemze ◽  
David J. Brinkman ◽  
Olaf Welting ◽  
Patricia H. P. van Hamersveld ◽  
Caroline Verseijden ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Nerve Stimulation ◽  
Vagus Nerve Stimulation ◽  
Inflammatory Cytokine ◽  
Dextran Sulfate ◽  
Dextran Sulfate Sodium ◽  
Innate Immune ◽  
Cytokine Levels ◽  
Colitis Model

Clinical trials suggest that vagus nerve stimulation presents an alternative approach to classical immune suppression in Crohn's disease. T cells capable of producing acetylcholine (ChAT+ T cells) in the spleen are essential mediators of the anti-inflammatory effect of vagus nerve stimulation. Besides the spleen, ChAT+ T cells are found abundantly in Peyer’s patches of the small intestine. However, the role of ChAT+ T cells in colitis pathogenesis is unknown. Here, we made use of CD4creChATfl/fl mice (CD4ChAT−/− mice) lacking ChAT expression specifically in CD4+ T cells. Littermates (ChATfl/fl mice) served as controls. In acute dextran sulfate sodium (DSS)-induced colitis (7 days of 2% DSS in drinking water), CD4ChAT−/− mice showed attenuated colitis and lower intestinal inflammatory cytokine levels compared with ChATfl/fl mice. In contrast, in a resolution model of DSS-induced colitis (5 days of 2% DSS followed by 7 days without DSS), CD4ChAT−/− mice demonstrated a worsened colitis recovery and augmented colonic histological inflammation scores and inflammatory cytokine levels as compared with ChATfl/fl mice. In a transfer colitis model using CD4+CD45RBhigh T cells, T cells from CD4ChAT−/− mice induced a similar level of colitis compared with ChATfl/fl T cells. Together, our results indicate that ChAT+ T cells aggravate the acute innate immune response upon mucosal barrier disruption in an acute DSS-induced colitis model, whereas they are supporting the later resolution process of this innate immune-driven colitis. Surprisingly, ChAT expression in T cells seems redundant in the context of T cell-driven colitis. NEW & NOTEWORTHY By using different mouse models of experimental colitis, we provide evidence that in dextran sulfate sodium-induced colitis, ChAT+ T cells capable of producing acetylcholine worsen the acute immune response, whereas they support the later healing phase of this innate immune-driven colitis.

scholarly journals Emerging Roles of Protein Deamidation in Innate Immune Signaling

2016 ◽  
Vol 90 (9) ◽  
pp. 4262-4268 ◽  
Author(s):  
Jun Zhao ◽  
Junhua Li ◽  
Simin Xu ◽  
Pinghui Feng
Keyword(s):  
Immune Responses ◽  
Innate Immune ◽  
Microbial Pathogens ◽  
Biological Processes ◽  
Innate Immune Responses ◽  
Immune Signaling ◽  
Host Immune Responses ◽  
Innate Immune Signaling ◽  
Enzyme Deficient ◽  
Signaling Components

Protein deamidation has been considered a nonenzymatic process associated with protein functional decay or “aging.” Recent studies implicate protein deamidation in regulating signal transduction in fundamental biological processes, such as innate immune responses. Work investigating gammaherpesviruses and bacterial pathogens indicates that microbial pathogens deploy deamidases or enzyme-deficient homologues (pseudoenzymes) to induce deamidation of key signaling components and evade host immune responses. Here, we review studies on protein deamidation in innate immune signaling and present several imminent questions concerning the roles of protein deamidation in infection and immunity.

scholarly journals 6,7,4′-Trihydroxyflavanone Protects against Dextran Sulfate Sodium-Induced Colitis by Regulating the Activity of T Cells and Colon Cells In Vivo

2021 ◽  
Vol 22 (4) ◽  
pp. 2083
Author(s):  
Hyun-Su Lee ◽  
Gil-Saeng Jeong
Keyword(s):  
T Cells ◽  
Dextran Sulfate ◽  
Dextran Sulfate Sodium ◽  
Cell Activity ◽  
Bioactive Molecules ◽  
Colon Cells ◽  
Colon Cell ◽  
Ht 29 ◽  
Colitis Model

Colitis is a multifactorial disorder that mostly occurs in the gastrointestinal tract. Despite improvements in mucosal inflammation research, little is known regarding the small bioactive molecules that are beneficial for regulating T cells and colon cell activity. 6,7,4′-trihydroxyflavanone (THF) is a flavanone that possesses anti-osteoclastogenesis activity and exerts protective effects against methamphetamine-induced immunotoxicity. Whether THF mitigates intestinal inflammation by regulating T cells and colon cell activity remains unknown. In the present study, Jurkat and HT-29 cells were used for in vitro experiments, and dextran sulfate sodium (DSS)-induced colitis model in mice was used for in vivo experiment. We observed that THF did not have a negative effect on the viability of Jurkat and HT-29 cells. Quantitative PCR and Western blot analysis revealed that THF regulates the activity of Jurkat cells and HT-29 cells via the NFκB and MAPK pathways under stimulated conditions. In the DSS-induced colitis model, oral administration of THF attenuated the manifestations of DSS-induced colitis, including a reduction in body weight, shrinkage of the colon, and enhanced expression of pro-inflammatory cytokines in the colon and mesenteric lymph nodes. These data suggest that THF alleviates DSS-induced colitis by modulating the activity of T cells and colon cells in vivo.

scholarly journals The RhoA-ROCK pathway in the regulation of T and B cell responses

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 2295 ◽  
Author(s):  
Edd Ricker ◽  
Luvana Chowdhury ◽  
Woelsung Yi ◽  
Alessandra B. Pernis
Keyword(s):  
Immune Responses ◽  
Biological Processes ◽  
Dynamic Interactions ◽  
Cell Responses ◽  
Important Mediator ◽  
Downstream Effectors ◽  
Wide Range ◽  
Response To Stress ◽  
The Impact ◽  
Rho Kinases

Effective immune responses require the precise regulation of dynamic interactions between hematopoietic and non-hematopoietic cells. The Rho subfamily of GTPases, which includes RhoA, is rapidly activated downstream of a diverse array of biochemical and biomechanical signals, and is emerging as an important mediator of this cross-talk. Key downstream effectors of RhoA are the Rho kinases, or ROCKs. The ROCKs are two serine-threonine kinases that can act as global coordinators of a tissue’s response to stress and injury because of their ability to regulate a wide range of biological processes. Although the RhoA-ROCK pathway has been extensively investigated in the non-hematopoietic compartment, its role in the immune system is just now becoming appreciated. In this commentary, we provide a brief overview of recent findings that highlight the contribution of this pathway to lymphocyte development and activation, and the impact that dysregulation in the activation of RhoA and/or the ROCKs may exert on a growing list of autoimmune and lymphoproliferative disorders.

scholarly journals Extracellular Vesicles Secreted by Mesenchymal Stromal Cells Exert Opposite Effects to Their Cells of Origin in Murine Sodium Dextran Sulfate-Induced Colitis

2021 ◽  
Vol 12 ◽  
Author(s):  
Anna Maria Tolomeo ◽  
Ignazio Castagliuolo ◽  
Martina Piccoli ◽  
Michele Grassi ◽  
Fabio Magarotto ◽  
...  
Keyword(s):  
Beneficial Effect ◽  
Extracellular Vesicles ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Dextran Sulfate ◽  
Experimental Colitis ◽  
Culture Conditions ◽  
Experimental Conditions ◽  
Intestinal Fibrosis ◽  
Cells Of Origin

Several reports have described a beneficial effect of Mesenchymal Stromal Cells (MSCs) and of their secreted extracellular vesicles (EVs) in mice with experimental colitis. However, the effects of the two treatments have not been thoroughly compared in this model. Here, we compared the effects of MSCs and of MSC-EV administration in mice with colitis induced by dextran sulfate sodium (DSS). Since cytokine conditioning was reported to enhance the immune modulatory activity of MSCs, the cells were kept either under standard culture conditions (naïve, nMSCs) or primed with a cocktail of pro-inflammatory cytokines, including IL1β, IL6 and TNFα (induced, iMSCs). In our experimental conditions, nMSCs and iMSCs administration resulted in both clinical and histological worsening and was associated with pro-inflammatory polarization of intestinal macrophages. However, mice treated with iEVs showed clinico-pathological improvement, decreased intestinal fibrosis and angiogenesis and a striking increase in intestinal expression of Mucin 5ac, suggesting improved epithelial function. Moreover, treatment with iEVs resulted in the polarization of intestinal macrophages towards and anti-inflammatory phenotype and in an increased Treg/Teff ratio at the level of the intestinal lymph node. Collectively, these data confirm that MSCs can behave either as anti- or as pro-inflammatory agents depending on the host environment. In contrast, EVs showed a beneficial effect, suggesting a more predictable behavior, a safer therapeutic profile and a higher therapeutic efficacy with respect to their cells of origin.

scholarly journals Redox Homeostasis and Metabolism in Cancer: A Complex Mechanism and Potential Targeted Therapeutics

2020 ◽  
Vol 21 (9) ◽  
pp. 3100 ◽  
Author(s):  
Alia Ghoneum ◽  
Ammar Yasser Abdulfattah ◽  
Bailey Olivia Warren ◽  
Junjun Shu ◽  
Neveen Said
Keyword(s):  
Cancer Cells ◽  
Cancer Progression ◽  
Metabolic Pathways ◽  
Redox Homeostasis ◽  
Ros Production ◽  
Biological Processes ◽  
Survival Pathways ◽  
Oncogenic Mutations ◽  
And Oxidative Stress ◽  
Shed Light

Reactive Oxygen Species or “ROS” encompass several molecules derived from oxygen that can oxidize other molecules and subsequently transition rapidly between species. The key roles of ROS in biological processes are cell signaling, biosynthetic processes, and host defense. In cancer cells, increased ROS production and oxidative stress are instigated by carcinogens, oncogenic mutations, and importantly, metabolic reprograming of the rapidly proliferating cancer cells. Increased ROS production activates myriad downstream survival pathways that further cancer progression and metastasis. In this review, we highlight the relation between ROS, the metabolic programing of cancer, and stromal and immune cells with emphasis on and the transcription machinery involved in redox homeostasis, metabolic programing and malignant phenotype. We also shed light on the therapeutic targeting of metabolic pathways generating ROS as we investigate: Orlistat, Biguandes, AICAR, 2 Deoxyglucose, CPI-613, and Etomoxir.

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