Environmental Microbial Factors Determine the Pattern of Inflammatory Lesions in a Murine Model of Crohn’s Disease–Like Inflammation

Stolzer, Iris; Kaden-Volynets, Valentina; Ruder, Barbara; Letizia, Marilena; Bittel, Miriam; Rausch, Philipp; Basic, Marijana; Baines, John F.; Wirtz, Stefan; Weidinger, Carl; Bischoff, Stephan C.; Becker, Christoph; Günther, Claudia

doi:10.1093/ibd/izz142

Cited by 28 publications

(22 citation statements)

References 58 publications

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“…Excess cell death in the intestinal epithelium resulting from dysregulated RIPK1 and RIPK3 signaling has been linked to intestinal inflammation, [61][62][63] and inducing necroptosis by deleting caspase-8 in IECs is sufficient to induce a lethal inflammatory disease in mice along with Paneth cell depletion. 64,65 We found that RIPK1/3 inhibition ameliorated GVHD and restored Paneth cells in allo-HCT recipient Atg16L1 DIEC mice. Based on these results in the animal model, we were remarkably able to design an ex vivo GVHD platform that reproduced the role of ATG16L1 in IECs.…”

Section: Discussionmentioning

confidence: 81%

An intestinal organoid–based platform that recreates susceptibility to T-cell–mediated tissue injury

Matsuzawa-Ishimoto¹,

Hine

Shono

et al. 2020

Blood

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A goal in precision medicine is to use patient-derived material to predict disease course and intervention outcomes. Here, we use mechanistic observations in a preclinical animal model to design an ex vivo platform that recreates genetic susceptibility to T-cell–mediated damage. Intestinal graft-versus-host disease (GVHD) is a life-threatening complication of allogeneic hematopoietic cell transplantation. We found that intestinal GVHD in mice deficient in Atg16L1, an autophagy gene that is polymorphic in humans, is reversed by inhibiting necroptosis. We further show that cocultured allogeneic T cells kill Atg16L1-mutant intestinal organoids from mice, which was associated with an aberrant epithelial interferon signature. Using this information, we demonstrate that pharmacologically inhibiting necroptosis or interferon signaling protects human organoids derived from individuals harboring a common ATG16L1 variant from allogeneic T-cell attack. Our study provides a roadmap for applying findings in animal models to individualized therapy that targets affected tissues.

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Section: Discussionmentioning

confidence: 81%

An intestinal organoid–based platform that recreates susceptibility to T-cell–mediated tissue injury

Matsuzawa-Ishimoto¹,

Hine

Shono

et al. 2020

Blood

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“…Some of these ileitis models (Samp/YitFc, Caspase‐8 ∆iec, and FADD ∆iec ) exhibit sterile inflammation which can be augmented by the presence of microbes. In models with sterile inflammation, the Paneth cells may undergo necrosis or necroptosis, which are inherently inflammatory (Stolzer et al, 2020). Inflammatory signals may also derive from danger‐associated molecular patterns (DAMPs) generated from defective autophagy and unfolded proteins (unfolded protein response; UPR) in Paneth cells with sub‐lethal distress (Cadwell et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Role of the microbiota in ileitis of a mouse model of inflammatory bowel disease—Glutathione peroxide isoenzymes 1 and 2‐double knockout mice on a C57BL background

et al. 2020

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“…In line with these studies it has been previously shown that mice lacking this central cell death regulator (Casp8 IEC ) in intestinal epithelial cells spontaneously develop intestinal inflammation with histomorphological alterations similar to the classical features of Crohn's disease. Accordingly, Casp8 IEC mice mimic several important characteristics including Paneth cell depletion accompanied by microbial dysbiosis, the culprit of inflammation in the ileum, as well as the immune cell signature (Th1 driven) association with elevated IFN levels (17)(18)(19). Inflammation in these mice is primarily located in the distal part of the small intestine (ileum), and depending on the microbial composition can vary in extent and localization to cause colitis or extensive enteritis (17,18).…”

Section: Introductionmentioning

confidence: 99%

“…Accordingly, Casp8 IEC mice mimic several important characteristics including Paneth cell depletion accompanied by microbial dysbiosis, the culprit of inflammation in the ileum, as well as the immune cell signature (Th1 driven) association with elevated IFN levels (17)(18)(19). Inflammation in these mice is primarily located in the distal part of the small intestine (ileum), and depending on the microbial composition can vary in extent and localization to cause colitis or extensive enteritis (17,18). Colonic inflammation is dependent on TNFα signaling, whereas TNFα deficiency is able to ameliorate colonic inflammation, but is not sufficient to prevent Paneth cell loss or enteritis in the small intestine (19,20).…”

Section: Introductionmentioning

confidence: 99%

An IFN-STAT Axis Augments Tissue Damage and Inflammation in a Mouse Model of Crohn's Disease

et al. 2021

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Blocking interferon-function by therapeutic intervention of the JAK-STAT-axis is a novel promising treatment option for inflammatory bowel disease (IBD). Although JAK inhibitors have proven efficacy in patients with active ulcerative colitis (UC), they failed to induce clinical remission in patients with Crohn's disease (CD). This finding strongly implicates a differential contribution of JAK signaling in both entities. Here, we dissected the contribution of different STAT members downstream of JAK to inflammation and barrier dysfunction in a mouse model of Crohn's disease like ileitis and colitis (Casp8ΔIEC mice). Deletion of STAT1 in Casp8ΔIEC mice was associated with reduced cell death and a partial rescue of Paneth cell function in the small intestine. Likewise, organoids derived from the small intestine of these mice were less sensitive to cell death triggered by IBD-key cytokines such as TNFα or IFNs. Further functional in vitro and in vivo analyses revealed the impairment of MLKL-mediated necrosis as a result of deficient STAT1 function, which was in turn associated with improved cell survival. However, a decrease in inflammatory cell death was still associated with mild inflammation in the small intestine. The impact of STAT1 signaling on gastrointestinal inflammation dependent on the localization of inflammation, as STAT1 is essential for intestinal epithelial cell death regulation in the small intestine, whereas it is not the key factor for intestinal epithelial cell death in the context of colitis. Of note, additional deletion of STAT2 was not sufficient to restore Paneth cell function but strongly ameliorated ileitis. In summary, we provide here compelling molecular evidence that STAT1 and STAT2, both contribute to intestinal homeostasis, but have non-redundant functions. Our results further demonstrate that STATs individually affect the distinct pathophysiology of inflammation in the ileum and colon, respectively, which might explain the diverse outcome of JAK inhibitors on inflammatory bowel diseases.

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Environmental Microbial Factors Determine the Pattern of Inflammatory Lesions in a Murine Model of Crohn’s Disease–Like Inflammation

Cited by 28 publications

References 58 publications

An intestinal organoid–based platform that recreates susceptibility to T-cell–mediated tissue injury

An intestinal organoid–based platform that recreates susceptibility to T-cell–mediated tissue injury

Role of the microbiota in ileitis of a mouse model of inflammatory bowel disease—Glutathione peroxide isoenzymes 1 and 2‐double knockout mice on a C57BL background

An IFN-STAT Axis Augments Tissue Damage and Inflammation in a Mouse Model of Crohn's Disease

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