Necroptosis Is Active in Children With Inflammatory Bowel Disease and Contributes to Heighten Intestinal Inflammation

Pierdomenico, Maria; Negroni, Anna; Stronati, Laura; Vitali, Roberta; Prete, Enrica; Bertin, John; Gough, Peter J.; Aloi, Marina; Cucchiara, Salvatore

doi:10.1038/ajg.2013.403

Cited by 176 publications

(154 citation statements)

References 33 publications

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“…Unlike programmed apoptotic cell death, which resolves inflammation, necroptosis is associated with non-resolving inflammation and persistent activation of stress kinases such as JNK (41,42). As a consequence, cell necroptosis is associated with a multitude of inflammatory complications such as atherosclerosis, reduced wound repair, inflammatory bowel diseases, and ischemic injury (13,(42)(43)(44)(45)(46). Our finding that a super-low dose of endotoxin elicits cell necroptosis potentially explains the detrimental effect of superlow-grade endotoxemia in humans.…”

Section: Discussionmentioning

confidence: 80%

Molecular and Cellular Mechanisms Responsible for Cellular Stress and Low-grade Inflammation Induced by a Super-low Dose of Endotoxin

Baker¹,

Maitra²,

Geng

et al. 2014

Journal of Biological Chemistry

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Background: Low-grade endotoxemia is a risk factor for chronic non-resolving inflammatory diseases. Results: A super-low dose of LPS induces cellular stress, mitochondrial fission, and necroptosis. Conclusion: IRAK-1 is required for cellular and molecular events leading to mitochondrial fission and cellular necroptosis. Significance: This study reveals novel mechanisms responsible for cellular stress, necroptosis, and low-grade inflammation associated with low-grade endotoxemia.

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Section: Discussionmentioning

confidence: 80%

Molecular and Cellular Mechanisms Responsible for Cellular Stress and Low-grade Inflammation Induced by a Super-low Dose of Endotoxin

Baker¹,

Maitra²,

Geng

et al. 2014

Journal of Biological Chemistry

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“…6C). Necroptosis can be induced after the inhibition or loss expression of caspase-8 which triggers the phosphorylation of RIP1 and RIP3 [17]. We therefore analyzed the expression of active caspase-8 after celastrol treatment, and the results showed that active caspase-8 level was significantly increased in the celastrol group compared to the saline group (Fig.…”

Section: Celastrol Suppressed Necroptosis By Inhibiting the Rip3/mlklmentioning

confidence: 93%

The natural compound celastrol inhibits necroptosis and alleviates ulcerative colitis in mice

Jia

Shen

et al. 2015

International Immunopharmacology

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“…Marion et al reported sensitization of keratinocytes to RIP3-mediated necrosis as a potent mechanism triggering skin inflammation and proposed that factors sensitizing keratinocytes to programmed necrosis could contribute to inflammatory skin diseases and chronic inflammation (Bonnet et al, 2013). Several reports suggest that high expression of RIP3 functions in inflammatory disease pathogenesis (Wu et al, 2012;Pierdomenico et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Upregulated RIP3 Expression Potentiates MLKL Phosphorylation–Mediated Programmed Necrosis in Toxic Epidermal Necrolysis

Kim

Yoon

et al. 2015

Journal of Investigative Dermatology

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Toxic epidermal necrolysis (TEN) is a severe adverse drug reaction involving extensive keratinocyte death in the epidermis. Histologically, the skin from TEN patients exhibits separation at the dermo-epidermal junction and accompanying necrosis of epidermal keratinocytes. Receptor-interacting protein kinase-3 (RIP3 or RIPK3) is an essential part of the cellular machinery that executes "programmed", or "regulated", necrosis and has a key role in spontaneous cell death and inflammation in keratinocytes under certain conditions. Here we show that RIP3 expression is highly upregulated in skin sections from TEN patients and may therefore contribute to the pathological damage in TEN through activation of programmed necrotic cell death. The expression level of mixed lineage kinase domain-like protein (MLKL), a key downstream component of RIP3, was not significantly different in skin lesions of TEN. However, elevated MLKL phosphorylation was observed in the skin from TEN patients, indicating the presence of RIP3-dependent programmed necrosis. Importantly, in an in vitro model of TEN, dabrafenib, an inhibitor of RIP3, prevented RIP3-mediated MLKL phosphorylation and decreased cell death. Results from this study suggest that the high expression of RIP3 in keratinocytes from TEN patients potentiates MLKL phosphorylation/activation and necrotic cell death. Thus, RIP3 represents a potential target for treatment of TEN.

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Necroptosis Is Active in Children With Inflammatory Bowel Disease and Contributes to Heighten Intestinal Inflammation

Abstract: We show for the first time that necroptosis is strongly associated with intestinal inflammation in children with IBD and contributes to strengthen the inflammatory process. We believe that RIP3 and MLKL could represent attractive targets for the management of human IBD.

Cited by 176 publications

References 33 publications

Molecular and Cellular Mechanisms Responsible for Cellular Stress and Low-grade Inflammation Induced by a Super-low Dose of Endotoxin

Molecular and Cellular Mechanisms Responsible for Cellular Stress and Low-grade Inflammation Induced by a Super-low Dose of Endotoxin

The natural compound celastrol inhibits necroptosis and alleviates ulcerative colitis in mice

Upregulated RIP3 Expression Potentiates MLKL Phosphorylation–Mediated Programmed Necrosis in Toxic Epidermal Necrolysis

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