19 ROLE OF IL-33 IN PURINE METABOLISM AND ILC2 ACTIVATION DURING COLITIS-ASSOCIATED CANCER

2020 ◽  
Vol 26 (Supplement_1) ◽  
pp. S34-S34
Author(s):  
Carlo De Salvo ◽  
Kristine-Ann Buela ◽  
Hannah Havran ◽  
Theresa Pizarro
Keyword(s):  
Flow Cytometry ◽  
Cell Population ◽  
Intestinal Inflammation ◽  
Inflammatory Diseases ◽  
Purine Metabolism ◽  
Lymphoid Cells ◽  
Mesenteric Lymph Nodes ◽  
Increased Risk ◽  
A Cell ◽  
Deficient Mice

Abstract UC patients have an increased risk of developing colorectal cancer, however, the immune cells and cytokines that mediate the transition from intestinal inflammation to cancer are poorly understood. Mucosal IL-33 is increased in UC patients, in addition, IL-33 and its receptor, ST2, are expressed in polyps in AOM/DSS models of colitis-associated cancer (CAC). Therefore, several studies have implicated IL-33, which is also an important activator of Innate Lymphoid Cells type 2 (ILC2s), in the formation of tumors. Moreover, it has been shown that ecto-5’-nucleotidase (CD73), critical ectoenzyme in purine metabolism which hydrolyzes extracellular AMP to adenosine, is upregulated in cancerous tissues, and an incompetent purine metabolic pathway has been associated with inflammation and inappropriate resolution in numerous inflammatory diseases, including IBD. In order to induce colitis-associated polyposis, we performed AOM/DSS protocol on 10-wk-old C57BL/6, IL-33KO and CD73KO mice as follow: the carcinogen Azoxymethane (AOM) was injected intraperitoneally (i.p.) on day 0. After two weeks, 3% dextran sodium sulfate (DSS) was administered in drinking water for a week, followed by two weeks of recovery with normal water. DSS administration and recovery was repeated one more time before euthanizing mice for tissue collection and analysis. Flow cytometry analysis showed that all ILC2s, and more specifically CD73 expressing ILC2s were significantly decreased in mesenteric lymph nodes (MLNs) of AOM/DSS treated mice lacking IL-33, compared to WT, on the other hand, CD73 deficient mice displayed a strongly reduced number of polyps compared to WT and flow cytometry revealed an ST2 expressing ILC2 cell population that was markedly reduced in CD73 deficient mice in comparison to WT. We next injected AOM/DSS treated C57BL/6 mice with either inhibitor of CD73 or sodium polyoxotungstate 1 (POM-1) CD39 inhibitor, therefore targeting the key enzymes in the purine metabolism pathway. We injected the mice i.p. with 10 mg per Kg body weight per day of either compounds or PBS, every day during the 2 weeks of DSS, to mimic a possible therapeutic treatment to prevent purine metabolism-depentent CAC. Histologic investigation of colon tissues isolated from mice treated with CD39 or CD73 inhibitors showed a significant decrease in inflammation and polyp numbers compared to vehicle-treated mice. The data so far collected suggest that a cell population of CD73 expressing ILC2s is involved in polyp formation in AOM/DSS-treated mice and that ILC2s expansion and activity depends on IL-33/ST2 and purine metabolism synergy. Therefore the possibility exists that blockade of IL-33/ST2 axis and purine metabolism might be effective in reducing ILC2s expansion and thus be beneficial in preventing or reducing early events promoting CAC.

scholarly journals Role of the High Affinity Immunoglobulin E Receptor in Bacterial Translocation and Intestinal Inflammation

2000 ◽  
Vol 193 (1) ◽  
pp. 25-34 ◽  
Author(s):  
David Dombrowicz ◽  
Sophie Nutten ◽  
Pierre Desreumaux ◽  
Christel Neut ◽  
Gérard Torpier ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Bacterial Translocation ◽  
Intestinal Inflammation ◽  
Immunoglobulin E ◽  
Interleukin 4 ◽  
Mesenteric Lymph Nodes ◽  
Bacterial Pathogenicity ◽  
High Affinity ◽  
High Affinity Receptor ◽  
A Cell

A role for immunoglobulin E and its high affinity receptor (FcεRI) in the control of bacterial pathogenicity and intestinal inflammation has been suggested, but relevant animal models are lacking. Here we compare transgenic mice expressing a humanized FcεRI (hFcεRI), with a cell distribution similar to that in humans, to FcεRI-deficient animals. In hFcεRI transgenic mice, levels of colonic interleukin 4 were higher, the composition of fecal flora was greatly modified, and bacterial translocation towards mesenteric lymph nodes was increased. In hFcεRI transgenic mice, 2,4,6-tri-nitrobenzenesulfonic acid (TNBS)-induced colitis was also more pronounced, whereas FcεRI-deficient animals were protected from colitis, demonstrating that FcεRI can affect the onset of intestinal inflammation.

scholarly journals Are Patients with Inflammatory Bowel Disease at Increased Risk for Covid-19 Infection?

2020 ◽  
Vol 14 (9) ◽  
pp. 1334-1336 ◽  
Author(s):  
Giovanni Monteleone ◽  
Sandro Ardizzone
Keyword(s):  
Intestinal Inflammation ◽  
Inflammatory Diseases ◽  
Convincing Evidence ◽  
Complex Interaction ◽  
The Novel ◽  
Relevant Today ◽  
Increased Risk ◽  
Bowel Diseases ◽  
Patients At Risk ◽  
Inflammatory Bowel

Abstract Crohn’s disease [CD] and ulcerative colitis [UC], the main inflammatory bowel diseases [IBD] in humans, are chronic, immune-inflammatory diseases, the pathogenesis of which suggests a complex interaction between environmental factors and genetic susceptibility. These disabling conditions affect millions of individuals and, together with the drugs used to treat them, can put patients at risk of developing complications and other conditions. This is particularly relevant today, as coronavirus disease [Covid-19] has rapidly spread from China to countries where IBD are more prevalent, and there is convincing evidence that Covid-19-mediated morbidity and mortality are higher in subjects with comorbidities. The primary objectives of this Viewpoint are to provide a focused overview of the factors and mechanisms by which the novel severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] infects cells and to illustrate the link between such determinants and intestinal inflammation. We also provide clues about the reasons why the overall IBD population might have no increased risk of developing SARS-CoV-2 infection and highlight the potential of cytokine blockers, used to treat IBD patients, to prevent Covid-driven pneumonia.

scholarly journals SAT0025 NEUROMEDIN U SUPPRESSES COLLAGEN-INDUCED ARTHRITIS THROUGH ACTIVATION OF ILC2

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 942.2-942
Author(s):  
Y. Zhang ◽  
Y. Qin ◽  
Z. Chen
Keyword(s):  
Flow Cytometry ◽  
Molecular Mechanisms ◽  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
Th2 Cells ◽  
Repeated Injection ◽  
Collagen Induced Arthritis ◽  
Clinical Onset ◽  
Deficient Mice

Background:Reduction and dysregulation of ILC2 was linked to delayed resolution of arthritis. The neuropeptide Neuromedin U (NMU) has been reported to rapidly activate ILC2 and initiate a Th2 type immune response through NMUR1 expressed on the surface of ILC2. However, one previous study reported that NMU promoted autoantibody-mediated arthritis.Objectives:The aim of this work was to investigate the effect of NMU on collagen-induced arthritis (CIA) mice and the potential mechanisms.Methods:CIA was induced in C57BL/6 WT and C57BL/6Nmudeficient mice on day 1. WT mice were treated i.p. daily by NMU-23 (20ug/mice) or by PBS for 10 days from day 1 to 5 and day 21 to 25. The clinical scores of CIA mice were assessed every two days from day 22 and determined on a scale of 0–4 for each paw. The proportion of ILC2 as well as Th1, Th2, Th17 and Treg in spleen, mesenteric lymph node (mLN) and joints of arthritic mice were analyzed by flow cytometry on day 42.Results:NMU-23 dramatically inhibited clinical onset and severity of arthritis in treated WT mice compared with control mice. Interestingly, NMU-deficient mice also developed significantly less severe arthritis compared with WT control (Fig 1). Flow cytometry analyses showed that the proportion of ILC2, which defined as Lin-CD45+CD127+KLRG1+ICOS+ST2+, was elevated in the joint but not in the spleen and mLN of arthritic mice treated with NMU-23. In contrast, the proportion of ILC2 was significantly lower in the spleen of NMU-deficient mice than WT control. The percentage of Th2 cells in the spleen and mLN tend to be higher in NMU-23 treated mice, but there is no statistical significance. Surprisingly, Th1 cells were increased in the mLN of NMU-23 treated and NMU-deficient mice compared with control whereas Th17 was comparable among groups. In addition, the proportion of Treg was decreased in the joint of NMU-23 treated and NMU-deficient mice compared with control mice.Conclusion:Our preliminary results show that repeated injection of NMU-23 during induction (early) and development (late) stage of CIA strongly suppressed clinical onset and severity of arthritis, which might be ascribed to activation of ILC2 in the joint. Further study is needed to explore other cellular and molecular mechanisms in the effect.References:[1] Cardoso V, Chesne J, Ribeiro H et al (2017) Neuronal regulation of type 2 innate lymphoid cells via neuromedin U. Nature 549 (7671):277-281.[2] Klose CSN, Mahlakoiv T, Moeller JB et al (2017) The neuropeptide neuromedin U stimulates innate lymphoid cells and type 2 inflammation. Nature 549 (7671):282-286.[3] Wallrapp A, Riesenfeld SJ, Burkett PR et al (2017) The neuropeptide NMU amplifies ILC2-driven allergic lung inflammation. Nature 549 (7672):351-356.[4] Sindhuja M Rao, Jennifer L Auger, Philippe Gaillard et al (2012) The Neuropeptide Neuromedin U Promotes Autoantibody-Mediated Arthritis. Arthritis Res Ther, 14 (1), R29.Disclosure of Interests:None declared

scholarly journals DEVELOPMENT OF CHICKEN LYMPHOID SYSTEM

1972 ◽  
Vol 135 (5) ◽  
pp. 1133-1150 ◽  
Author(s):  
Yong Sung Choi ◽  
Robert A. Good
Keyword(s):  
Molecular Weight ◽  
Cell Population ◽  
Gel Electrophoresis ◽  
Lymphoid Cells ◽  
Spleen Cells ◽  
Lymphoid System ◽  
A Cell ◽  
Thymus Cells

Synthesis and secretion of Ig by chicken lymphoid cells was studied. Both spleen and bursa cells synthesize and secrete IgM and IgG whereas Ig was not detected in thymus cells. In contrast to the spleen cells which synthesize H and L chains in balanced quantities, the bursa cells synthesize and secrete free L chains. In addition to the lymphoid cells which secrete IgM or IgG, the bursa appears to contain a cell population which synthesizes nonsecretory Ig. The structure of this Ig was studied by specific serological precipitation and by SDS-acrylamide gel electrophoresis. The H chains of this nonsecretory Ig are serologically related to µ-chains and exhibit a smaller molecular weight (i.e., ∼50,000) in SDS-acrylamide gel electrophoresis than H chains of IgG and IgM synthesized by the spleen cells (i.e., ∼70,000).

IL-2-deficient mice raised under germfree conditions develop delayed mild focal intestinal inflammation

1999 ◽  
Vol 276 (6) ◽  
pp. G1461-G1472 ◽  
Author(s):  
Michael Schultz ◽  
Susan L. Tonkonogy ◽  
Rance K. Sellon ◽  
Claudia Veltkamp ◽  
Virginia L. Godfrey ◽  
...  
Keyword(s):  
Intestinal Inflammation ◽  
Bacterial Colonization ◽  
Interleukin 2 ◽  
Portal Tract ◽  
Genetically Engineered ◽  
B Cell Differentiation ◽  
Hepatic Inflammation ◽  
Mesenteric Lymph Nodes ◽  
Viable Bacteria ◽  
Deficient Mice

Interleukin-2 (IL-2) amplifies immune stimuli and influences B cell differentiation. IL-2-deficient mice spontaneously develop intestinal inflammation if raised under specific pathogen-free (SPF) conditions. We quantitatively determined the aggressiveness and kinetics of gastrointestinal and hepatic inflammation in the presence or absence of viable bacteria in IL-2-deficient mice. Breeding colonies were maintained under SPF and germfree (GF) conditions. Intestinal tissues, serum, and mesenteric lymph nodes were obtained from mice at different ages for blind histological scoring, immunoglobulin measurements, mucosal T cell infiltration, and cytokine secretion. GF IL-2 −/− mice developed mild, focal, and nonlethal intestinal inflammation with delayed onset, whereas the more aggressive inflammation in SPF IL-2 −/− mice led to their death between 28 and 32 wk. Periportal hepatic inflammation was equal in the presence or absence of bacterial colonization. Intestinal immunoglobulin secretion decreased significantly by 13 wk of age in IL-2 −/− mice in both GF and SPF environments. In contrast to other genetically engineered rodents, IL-2 −/− mice develop mild focal gastrointestinal and active portal tract inflammation in the absence of viable bacteria.

scholarly journals A Cell Proliferation and Inflammatory Signature is Induced by Lawsonia intracellularis Infection in Swine

2018 ◽  
Author(s):  
Fernando L. Leite ◽  
Juan E. Abrahante ◽  
Erika Vasquez ◽  
Fabio Vannucci ◽  
Connie J. Gebhart ◽  
...  
Keyword(s):  
Host Response ◽  
Cellular Proliferation ◽  
Intestinal Inflammation ◽  
Inflammatory Diseases ◽  
Mammalian Species ◽  
Transglutaminase 2 ◽  
Oncostatin M ◽  
Lawsonia Intracellularis ◽  
Matrix Metalloproteinase 7 ◽  
A Cell

AbstractLawsonia intracellularis causes porcine proliferative enteropathy. This is an enteric disease characterized by thickening of the wall of the ileum that leads to decreased growth and diarrhea of animals. In this study, we investigated the host response to L. intracellularis infection by performing transcriptomic and pathway analysis of intestinal tissue in groups of infected and non-infected animals at 14, 21 and 28 days post challenge. At the peak of infection, when animals developed most severe lesions, infected animals expressed higher levels of several genes involved in cellular proliferation and inflammation including matrix metalloproteinase-7 (MMP7), transglutaminase-2 (TGM2) and Oncostatin M (OSM). Histomorphology also revealed general features of intestinal inflammation. This study identified important pathways associated with the host response in developing and resolving lesions due to L. intracellularis infection.ImportanceLawsonia intracellularis is among the most important enteric pathogens of swine and it can also infect other mammalian species. Much is still unknown regarding its pathogenesis and the host response, especially at the site of infection. In this study we uncovered several novel genes and pathways associated with infection. These differentially expressed genes, in addition to histological changes in infected tissue, revealed striking similarities between L. intracellularis infection and cellular proliferation mechanisms described in some cancers and inflammatory diseases of the gastrointestinal tract. This research sheds important light into the pathogenesis of L. intracellularis and the host response associated with the lesions caused by infection.

scholarly journals Is LRRK2 the missing link between inflammatory bowel disease and Parkinson’s disease?

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Mary K. Herrick ◽  
Malú G. Tansey
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Immune Cells ◽  
Intestinal Inflammation ◽  
Inflammatory Diseases ◽  
Increased Risk ◽  
Increase Risk ◽  
Inflammatory Processes ◽  
Inflammatory Bowel ◽  
Peripheral Immune Cells

AbstractLinks that implicate the gastrointestinal system in Parkinson’s disease (PD) pathogenesis and progression have become increasingly common. PD shares several similarities with Crohn’s disease (CD). Intestinal inflammation is common in both PD and CD and is hypothesized to contribute to PD neuropathology. Mutations in leucine-rich repeat kinase 2 (LRRK2) are one of the greatest genetic contributors to PD. Variants in LRRK2 have also been associated with increased incidence of CD. Since its discovery, LRRK2 has been studied intensely in neurons, despite multiple lines of evidence showing that LRRK2 is highly expressed in immune cells. Based on the fact that higher levels of LRRK2 are detectable in inflamed colonic tissue from CD patients and in peripheral immune cells from sporadic PD patients relative to matched controls, we posit that LRRK2 regulates inflammatory processes. Therefore, LRRK2 may sit at a crossroads whereby gut inflammation and higher LRRK2 levels in CD may be a biomarker of increased risk for sporadic PD and/or may represent a tractable therapeutic target in inflammatory diseases that increase risk for PD. Here we will focus on reviewing how PD and CD share overlapping phenotypes, particularly in terms of LRRK2 in the context of the immune system, that could be targeted in future therapies.

scholarly journals CD1d-Dependent iNKT Cells Control DSS-Induced Colitis in a Mouse Model of IFNγ-Mediated Hyperinflammation by Increasing IL22-Secreting ILC3 Cells

2021 ◽  
Vol 22 (3) ◽  
pp. 1250
Author(s):  
Hyun Jung Park ◽  
Sung Won Lee ◽  
Luc Van Kaer ◽  
Seokmann Hong
Keyword(s):  
Intestinal Inflammation ◽  
Critical Role ◽  
Lymphoid Cells ◽  
Inkt Cell ◽  
Mesenteric Lymph Nodes ◽  
Inkt Cells ◽  
Mesenteric Lymph ◽  
Type 3

We have previously shown that CD1d-restricted iNKT cells suppress dysregulated IFNγ expression and intestinal inflammation in Yeti mice on the C57BL/6 background. Since type 3 innate lymphoid cells (ILC3s) in mesenteric lymph nodes (MLN) protect against intestinal inflammation in a CD1d-associated manner, we investigated whether crosstalk between iNKT cells and MLN ILC3s controls IFNγ-mediated intestinal inflammation in Yeti mice. We found that Yeti mice display increased levels of ILC3s and that iNKT cell deficiency in Yeti/CD1d KO mice decreases levels of IL22-producing ILC3s during DSS-induced colitis. This finding indicates that iNKT cells and ILC3s cooperate to regulate intestinal inflammation in Yeti mice. Yeti iNKT cells displayed a pronounced anti-inflammatory (IL4- or IL9-producing) phenotype during colitis. Their adoptive transfer to iNKT cell-deficient animals induced a significant increase in IL22 production by ILC3s, indicating that crosstalk between iNKT cells and ILC3s plays a critical role in modulating colitis in Yeti mice. Moreover, we showed that the IL9-producing subset of iNKT cells potently enhances IL22-producing ILC3s in vivo. Taken together, our results identify a central role of the iNKT cell-ILC3 axis in ameliorating IFNγ-mediated intestinal inflammation.

scholarly journals Identifying Therapeutic Targets for Sepsis Research: A Characterization Study of the Inflammatory Players in the Cecal Ligation and Puncture Model

2018 ◽  
Vol 2018 ◽  
pp. 1-17 ◽  
Author(s):  
Sara Nullens ◽  
Joris De Man ◽  
Chris Bridts ◽  
Didier Ebo ◽  
Sven Francque ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Lymph Nodes ◽  
Gastrointestinal Motility ◽  
Cecal Ligation ◽  
Therapeutic Targets ◽  
Cecal Ligation And Puncture ◽  
Mesenteric Lymph Nodes ◽  
Mucosal Permeability ◽  
Human Sepsis ◽  
Increased Risk

During sepsis, disturbed gastrointestinal motility and increased mucosal permeability can aggravate sepsis due to the increased risk of bacterial translocation. To help identify new therapeutic targets, there is a need for animal models that mimic the immunological changes in the gastrointestinal tract as observed during human sepsis. We therefore characterized in detail the gastrointestinal neuroimmune environment in the cecal ligation and puncture (CLP) model, which is the gold standard animal model of microbial sepsis. Mice were sacrificed at day 2 and day 7, during which gastrointestinal motility was assessed and cytokines were measured in the serum and the colon. In the spleen, lymph nodes, ileum, and colon, subsets of leukocyte populations were identified by flow cytometry. Septic animals displayed an impaired gastrointestinal motility at day 2 and day 7. Two days post-CLP, increased serum and colonic levels of proinflammatory cytokines were measured. Flow cytometry revealed an influx of neutrophils in the colon and ileum, increased numbers of macrophages in the spleen and mesenteric lymph nodes, and an enhanced number of mast cells in all tissues. At day 7 post-CLP, lymphocyte depletion was observed in all tissues coinciding with increased IL-10 and TGF-β levels, as well as increased colonic levels of IL-17A and IFN-γ. Thus, CLP-induced sepsis in mice results in simultaneous activation of pro- and anti-inflammatory players at day 2 and day 7 in different tissues, mimicking human sepsis.

scholarly journals GM-CSF drives dysregulated hematopoietic stem cell activity and pathogenic extramedullary myelopoiesis in experimental spondyloarthritis

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Daniel Regan-Komito ◽  
James W. Swann ◽  
Philippos Demetriou ◽  
E. Suzanne Cohen ◽  
Nicole J. Horwood ◽  
...  
Keyword(s):  
Intestinal Inflammation ◽  
Inflammatory Diseases ◽  
Cell Activity ◽  
Lymphoid Cells ◽  
Neutrophil Accumulation ◽  
Hematopoietic Stem ◽  
Gm Csf ◽  
Multipotent Progenitors ◽  
Target Organs ◽  
Stem Cell Activity

AbstractDysregulated hematopoiesis occurs in several chronic inflammatory diseases, but it remains unclear how hematopoietic stem cells (HSCs) in the bone marrow (BM) sense peripheral inflammation and contribute to tissue damage in arthritis. Here, we show the HSC gene expression program is biased toward myelopoiesis and differentiation skewed toward granulocyte-monocyte progenitors (GMP) during joint and intestinal inflammation in experimental spondyloarthritis (SpA). GM-CSF-receptor is increased on HSCs and multipotent progenitors, favoring a striking increase in myelopoiesis at the earliest hematopoietic stages. GMP accumulate in the BM in SpA and, unexpectedly, at extramedullary sites: in the inflamed joints and spleen. Furthermore, we show that GM-CSF promotes extramedullary myelopoiesis, tissue-toxic neutrophil accumulation in target organs, and GM-CSF prophylactic or therapeutic blockade substantially decreases SpA severity. Surprisingly, besides CD4+ T cells and innate lymphoid cells, mast cells are a source of GM-CSF in this model, and its pathogenic production is promoted by the alarmin IL-33.

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