Necroptosis in inflammatory bowel disease and other intestinal diseases

Li, Sha; Ning, Longgui; Lou, Xinhe; Xu, Guofan

doi:10.12998/wjcc.v6.i14.745

Cited by 40 publications

(30 citation statements)

References 45 publications

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“…19,20 This observation would suggest that apoptosis is a consequence of NEC rather than a cause of NEC, and raises the possibility that other pathways of cell death are involved. By contrast, necroptosis 21 is a highly inflammatory cell death pathway that has been linked to the pathogenesis of several diseases of mucosal inflammation, 22,23 including inflammatory bowel disease and allergic colitis in children, 24 and lethal ileitis during intestinal development. 25 Necroptosis is characterized by the activation of receptor-interacting protein kinases ([RIPK]1 and RIPK3), leading to the phosphorylation and plasma membrane translocation of mixed lineage kinase-like (MLKL) ( Figure 1A), 21 where it forms a pore complex allowing the massive release of proinflammatory damage-associated molecular patterns and the death of the cell.…”

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confidence: 99%

A Novel Role for Necroptosis in the Pathogenesis of Necrotizing Enterocolitis

Werts

Fulton

Ladd

et al. 2020

Cellular and Molecular Gastroenterology and Hepatology

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Necrotizing enterocolitis is a devastating disease of prematurity characterized by gram-negative bacteria colonization and enterocyte death. We identify a role of Toll-like receptor 4-mediated necroptosis of the intestinal epithelium as a precursor to necrotizing enterocolitis development. BACKGROUND & AIMS: Necrotizing enterocolitis (NEC) is a devastating disease of premature infants characterized by Toll-like receptor 4 (TLR4)-dependent intestinal inflammation and enterocyte death. Given that necroptosis is a proinflammatory cell death process that is linked to bacterial signaling, we investigated its potential role in NEC, and the mechanisms involved. METHODS: Human and mouse NEC intestine were analyzed for necroptosis gene expression (ie, RIPK1, RIPK3, and MLKL), and protein activation (phosphorylated RIPK3). To evaluate a potential role for necroptosis in NEC, the effects of genetic (ie, Ripk3 knockout or Mlkl knockout) or pharmacologic (ie, Nec1s) inhibition of intestinal inflammation were assessed in a mouse NEC model, and a possible upstream role of TLR4 was assessed in Tlr4-deficient mice. The NEC-protective effects of human breast milk and its constituent milk oligosaccharides on necroptosis were assessed in a NEC-in-a-dish model, in which mouse intestinal organoids were cultured as either undifferentiated or differentiated epithelium in the presence of NEC bacteria and hypoxia. RESULTS: Necroptosis was activated in the intestines of human and mouse NEC in a TLR4-dependent manner, and was upregulated specifically in differentiated epithelium of the immature ileum. Inhibition of necroptosis genetically and pharmacologically reduced intestinal-epithelial cell death and mucosal inflammation in experimental NEC, and ex vivo in the NEC-in-a-dish system. Strikingly, the addition of human breast milk, or the human milk oligosaccharide 2 fucosyllactose in the ex vivo system, reduced necroptosis and inflammation. CONCLUSIONS: Necroptosis is activated in the intestinal epithelium upon TLR4 signaling and is required for NEC development, and explains in part the protective effects of breast milk.

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confidence: 99%

A Novel Role for Necroptosis in the Pathogenesis of Necrotizing Enterocolitis

Werts

Fulton

Ladd

et al. 2020

Cellular and Molecular Gastroenterology and Hepatology

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“…Data from the present study identi ed that infection of macrophages with M. tuberculosis was associated with a lower level of FADD compared to M. bovis infection. FADD is an adapter protein to bind caspase 8 and caspase 10 precursors and is simultaneously activated and mediated cell signals with caspases 3, 6, and 7 to induce apoptosis [40]. This suggests that M. tuberculosis is able to inhibit signaling of caspases to execute the apoptosis.…”

Section: Discussionmentioning

confidence: 99%

The role of Mycobacterium tuberculosis complex species on apoptosis and necroptosis state of macrophages derived from active pulmonary tuberculosis patients

Yanti

Mulyadi²,

Amin

et al. 2020

Preprint

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Objective: The role of Mycobacterium tuberculosis complex (MTBC) species in tuberculosis (TB) infection in human is still questioned. The aim of this study was to determine whether M. tuberculosis and M. bovis is associated with apoptosis and necroptosis by measuring the expression of specific signaling pathways components (Fas-associated protein with death domain (FADD) and receptor interacting protein 3 (RIP3)), and the level of apoptosis. Results: We recruited 30 patients with pulmonary TB; 24 patients were infected with M. tuberculosis Beijing strain and six patients with M. bovis BCG strain. M. tuberculosis-infected patients were more likely to have severe lung damage compared to those infected with M. bovis (odds ratio [OR]: 7.60; 95% confidence interval [CI]: 1.07-54.09). M. tuberculosis infection was associated with lower expression of FADD and lower apoptosis level of macrophages compared to M. bovis. No significant different of RIP3 between MTBC species groups. In conclusion, M. tuberculosis Beijing strain was associated with severe pulmonary damage, inhibited FADD expression and reduced apoptosis level of macrophages derived from pulmonary TB patients. This suggests that the M. tuberculosis Beijing strain is potentially to be used as determinant of disease progressivity and tissue damage in TB cases.

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“…25 The pro-inflammatory character of necroptosis plays a role in intestinal tissue damage, as represented by increased Paneth cell death and reduced goblet cells. 3 One study found that the expression of RIPK3 and MLKL might be an indicator of disease activity in patients with IBD. 6 Another study with similar findings in pediatric patients with IBD regarded necroptosis as an event that occurred when inflammation had been established.…”

Section: F I G U R Ementioning

confidence: 99%

“…1,2 Necroptosis has been associated with IBD because it may result in intestinal inflammatory damage, including increased Paneth cell death and reduced goblet cells. 3 Receptor-interacting protein kinase 3 (RIPK3), a key mediator of necroptosis, is elevated significantly in patients with IBD. 4,5 The elevation was also associated with increased disease activity.…”

Section: Introductionmentioning

confidence: 99%

Intestinal vitamin D receptor signaling ameliorates dextran sulfate sodium‐induced colitis by suppressing necroptosis of intestinal epithelial cells

et al. 2020

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Vitamin D status is closely related to inflammatory bowel disease (IBD), but the mechanism has not been fully elucidated. This study explored the effect of intestinal vitamin D signaling on necroptosis and the underlying mechanism in colitis. Serum 25(OH)D levels and the expression of necroptotic proteins were examined in patients with IBD. Colitis was induced in an intestinal‐specific hVDR transgenic model, and the gross manifestation, histological integrity, and intestinal barrier function were tested. The findings were further confirmed in vitro. Immunoprecipitation and colocalization were performed to investigate the association between the vitamin D receptor and necroptotic proteins. We found that serum 25(OH)D decreased in patients with IBD, while the expression of necroptotic proteins increased. The intestinal hVDR transgenic model could largely ameliorate the structural destruction, restore barrier dysfunction, and suppress necroptosis caused by DSS. This was probably achieved by binding to RIPK1/3 necrosomes, as we observed decreased RIPK1/3 necrosome formation and increased VDR expression in the cytosol. This study demonstrated an inhibitory effect of the intestinal vitamin D signaling pathway on necroptosis in DSS‐induced colitis. The vitamin D receptor shifts from the nucleus to the cytosol to impede the formation of RIPK1/3. Our findings may offer some theoretical basis for a novel treatment of IBD in clinical practice.

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Necroptosis in inflammatory bowel disease and other intestinal diseases

Cited by 40 publications

References 45 publications

A Novel Role for Necroptosis in the Pathogenesis of Necrotizing Enterocolitis

A Novel Role for Necroptosis in the Pathogenesis of Necrotizing Enterocolitis

The role of Mycobacterium tuberculosis complex species on apoptosis and necroptosis state of macrophages derived from active pulmonary tuberculosis patients

Intestinal vitamin D receptor signaling ameliorates dextran sulfate sodium‐induced colitis by suppressing necroptosis of intestinal epithelial cells

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