Fr482 BI 706039 IS A POTENT AND SELECTIVE INHIBITOR OF RIPK2 AND IMPROVES INTESTINAL INFLAMMATION IN THE TRUC MOUSE MODEL OF INFLAMMATORY BOWEL DISEASE.

Animal model of intestinal inflammation is of paramount significance that aids in discerning the pathologies underlying ulcerative colitis and Crohn’s disease, the two clinical presentations of inflammatory bowel disease. The 2,4,6-trinitrobenzene sulfonic acid (TNBS) colitis model represents one such intestinal inflammation-prototype that is generated in susceptible strains of mice through intra-rectal instillation of compound TNBS. In this paper, we demonstrate the experimental induction of TNBS-mediated colitis in a susceptible strain of ICR mice. This can be done by the following steps: a) acclimation, b) induction and c) observation. TNBS-mouse model provides the information in shortest possible time and simultaneously represents a cost effective and highly reproducible model method of studying the pathogenesis of inflammatory bowel disease.Video Clips<a href="https://youtube.com/v/6MsuIGzH3uA">Acclimation and induction of TNBS</a>: 4.5 min<a href="https://youtube.com/v/ya66SNwoVag">Observation and drug administration</a>: 1.5 min

Download Full-text

GPR4 Deficiency Alleviates Intestinal Inflammation in a Mouse Model of Inflammatory Bowel Disease

10.1101/059014 ◽

2016 ◽

Author(s):

Edward J. Sanderlin ◽

Nancy R. Leffler ◽

Kvin Lertpiriyapong ◽

Qi Cai ◽

Heng Hong ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Mouse Model ◽

Bowel Disease ◽

Intestinal Inflammation ◽

Vascular Endothelial Cells ◽

Leukocyte Adhesion ◽

Lymphoid Follicle ◽

Wild Type ◽

Inflammatory Bowel ◽

Deficient Mice

AbstractGPR4 is a proton-sensing G protein-coupled receptor that can be activated by extracellular acidosis. It has recently been demonstrated that activation of GPR4 by acidosis increases the expression of numerous inflammatory and stress response genes in vascular endothelial cells (ECs) and also augments EC-leukocyte adhesion. Inhibition of GPR4 by siRNA or small molecule inhibitors reduces endothelial cell inflammation. As acidotic tissue microenvironments exist in many types of inflammatory disorders, including inflammatory bowel disease (IBD), we examined the role of GPR4 in IBD using a dextran sulfate sodium (DSS)-induced colitis mouse model. We observed that GPR4 mRNA expression was increased in mouse and human IBD tissues when compared to control intestinal tissues. To determine the function of GPR4 in IBD, wild-type and GPR4-deficient mice were treated with 3% DSS for 7 days to induce acute colitis. Our results showed that the severity of colitis was decreased in GPR4-deficient DSS-treated mice in comparison to wild-type DSS-treated mice. Clinical parameters, macroscopic disease indicators, and histopathological features were less severe in the DSS-treated GPR4-deficient mice than the DSS-treated wild-type mice. Inflammatory gene expression, leukocyte infiltration, and isolated lymphoid follicle (ILF) formation were reduced in intestinal tissues of DSS-treated GPR4-null mice. Collectively, our results suggest GPR4 provides a pro-inflammatory role in IBD as the absence of GPR4 ameliorates intestinal inflammation in the acute DSS-induced IBD mouse model.

Download Full-text

The potent and selective RIPK2 inhibitor BI 706039 improves intestinal inflammation in the TRUC mouse model of Inflammatory Bowel Disease

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00163.2021 ◽

2021 ◽

Author(s):

Joerg Ermann ◽

Mederbek Matmusaev ◽

Emma Haley ◽

Clemens Braun ◽

Felix Jost ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Mouse Model ◽

Bowel Disease ◽

Intestinal Inflammation ◽

Intestinal Microbiome ◽

Intestinal Immune System ◽

Pharmacokinetic Properties ◽

Inflammatory Bowel ◽

The Impact ◽

Human And Mouse

ABSTRACT Background and Aims : Mouse and human data implicates the NOD1 and NOD2 sensors of the intestinal microbiome and the associated signal transduction via the RIPK2 kinase as a potentially key signaling node for the development of Inflammatory Bowel Disease (IBD) and an attractive target for pharmacologic intervention. The TRUC mouse model of IBD has been strongly indicated for evaluating the impact of RIPK2 antagonism on intestinal inflammation based on previous studies with NOD1, NOD2 and RIPK2 knockout mice. Methods. We identified and profiled the BI 706039 molecule as a potent and specific functional inhibitor of both human and mouse RIPK2 and with favorable pharmacokinetic properties. We dosed BI 706039 in the spontaneous TRUC mouse model from aged day 28 through aged day 56. Results : Oral, daily administration of BI 706039 caused dose-responsive and significant improvement in colonic histopathological inflammation, colon weight and terminal levels of protein normalized fecal lipocalin (all p< 0.001). These observations correlated with dose-responsively increasing systemic levels of the BI 706039 compound, splenic molecular target engagement of RIPK2 and modulation of inflammatory genes in the colon. Conclusions : A relatively low oral dose of a potent and selective RIPK2 inhibitor can block the signaling interface between the intestinal microbiome and the intestinal immune system and significantly improve disease associated intestinal inflammation.

Download Full-text

Intestinal inflammation and altered gut microbiota associated with inflammatory bowel disease renders mice susceptible to Clostridioides difficile colonization and infection

10.1101/2020.07.30.230094 ◽

2020 ◽

Author(s):

Lisa Abernathy Close ◽

Madeline R Barron ◽

James M George ◽

Michael G Dieterle ◽

Kimberly C Vendrov ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Mouse Model ◽

Gut Microbiota ◽

Bowel Disease ◽

Intestinal Inflammation ◽

Helicobacter Hepaticus ◽

Colonization Resistance ◽

Distal Intestine ◽

Clostridioides Difficile ◽

Inflammatory Bowel

Clostridioides difficile has emerged as a noteworthy pathogen in patients with inflammatory bowel disease (IBD). Concurrent IBD and CDI is associated with increased morbidity and mortality compared to CDI alone. IBD is associated with alterations of the gut microbiota, an important mediator of colonization resistance to C. difficile. Here, we describe and utilize a mouse model to explore the role of intestinal inflammation in susceptibility to C. difficile colonization and subsequent disease severity in animals with underlying IBD. Helicobacter hepaticus, a normal member of the mouse gut microbiota, was used to trigger inflammation in the distal intestine akin to human IBD in mice that lack intact IL-10 signaling. Development of IBD resulted in a distinct intestinal microbiota community compared to non-IBD controls. We demonstrate that in this murine model, IBD was sufficient to render mice susceptible to C. difficile colonization. Mice with IBD were persistently colonized by C. difficile, while genetically identical non-IBD controls were resistant to C. difficile colonization. Concomitant IBD and CDI was associated with significantly worse disease than unaccompanied IBD. IL-10-deficient mice maintained gut microbial diversity and colonization resistance to C. difficile in experiments utilizing an isogenic mutant of H. hepaticus that does not trigger intestinal inflammation. These studies in mice demonstrate that the IBD-induced microbiota is sufficient for C. difficile colonization and that this mouse model requires intestinal inflammation for inducing susceptibility to CDI in the absence of other perturbations, such as antibiotic treatment.

Download Full-text

Restored macrophage function ameliorates disease pathophysiology in a mouse model for IL10 receptor deficient very early onset inflammatory bowel disease

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjab031 ◽

2021 ◽

Author(s):

Mania Ackermann ◽

Adele Mucci ◽

Amanda McCabe ◽

Sandy Frei ◽

Kayla Wright ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Mouse Model ◽

Bowel Disease ◽

Early Onset ◽

Intestinal Inflammation ◽

Inflammatory Responses ◽

Intraperitoneal Administration ◽

Gene Correction ◽

Hematopoietic Stem ◽

Inflammatory Bowel

Abstract Background and aims Mutations in IL10 or the IL10-receptor lead to very early onset (VEO) inflammatory bowel disease (IBD), a life-threatening disease which is often unresponsive to conventional medication. Recent studies have demonstrated that defective IL-10 receptor signaling in innate immune cells is a key driver of severe intestinal inflammation in VEO-IBD. Specifically, IL10 unresponsiveness of macrophages, which govern the tight balance between pro- and anti-inflammatory responses in the intestinal system, plays a central role in the events leading to excessive inflammatory responses and the development of IBD. Methods and Results We here evaluated hematopoietic stem cell gene therapy in a VEO-IBD mouse model and demonstrate that the therapeutic response closely correlates with gene correction of the IL-10 signaling pathway in intestinal macrophages. This finding prompted us to evaluate the therapeutic efficacy of macrophage transplantation in the Il10rb -/- VEO-IBD mouse model. A 6-week regimen employing a combination of depletion of endogenous hyperinflammatory macrophages followed by intraperitoneal administration of wild-type macrophages significantly reduced colitis symptoms. Conclusion In summary, we show that the correction of the IL10 receptor-defect in macrophages either by genetic therapy or transfer of WT macrophages to the peritoneum can ameliorate disease-related symptoms and potentially represent novel treatment approaches for VEO-IBD patients.

Download Full-text