NEMO Prevents RIP Kinase 1-Mediated Epithelial Cell Death and Chronic Intestinal Inflammation by NF-κB-Dependent and -Independent Functions

Vlantis, Katerina; Wullaert, Andy; Polykratis, Apostolos; Kondylis, Vangelis; Dannappel, Marius; Schwarzer, Robin; Welz, Patrick-Simon; Corona, Teresa; Walczak, Henning; Weih, Falk; Klein, Ulf; Kelliher, Michelle A.; Pasparakis, Manolis

doi:10.1016/j.immuni.2016.02.020

Cited by 167 publications

(191 citation statements)

References 37 publications

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“…Mice lacking NEMO in IECs develop spontaneous colitis in SPF but not germ-free conditions, supporting the critical role of microbiota (27). Further investigation reveals that NEMO prevents Paneth cell and colonic epithelial cell death by activating NF-κB and inhibiting RIPK1 kinase activity respectively (27). …”

Section: Innate Sensors and Immune Signalingmentioning

confidence: 80%

Novel insights into microbiome in colitis and colorectal cancer

Yang¹,

Jobin

2017

Current Opinion in Gastroenterology

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Purpose of review Microbiota is a major component of the etiology of inflammatory bowel diseases (IBD) and colorectal cancer (CRC). Here, we summarize key advances achieved the past 18 months (ending June 2017) toward a better understanding of the role of microbiota in colitis and CRC development. Recent findings Accumulating evidence shows the essential role of intestinal barrier function (e.g., mucus, IgA, LCN2, LYPD8) in protecting against bacteria-induced inflammation and tumor development. Numerous signaling pathways (e.g., TLRs, NLRs), metabolites (e.g., indole, bile acids, retinoic acid) and small non-coding RNAs (e.g., miRNA) have been identified as key mediators regulating host-microbe interactions in the intestine. Novel microbial drivers of colitis and tumorigenesis (e.g., Alistipes finegoldii, Atopobium parvalum, Peptostreptococcus anaerobius) have been identified and their disease-promoting activities have been described. Summary IBD-associated colorectal cancer results from a complex breakdown of communication between the host and its microbiota, involving barrier function, immune signaling and metabolites.

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Section: Innate Sensors and Immune Signalingmentioning

confidence: 80%

Novel insights into microbiome in colitis and colorectal cancer

Yang¹,

Jobin

2017

Current Opinion in Gastroenterology

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“…Importantly, this checkpoint was recently demonstrated to be critical for regulating inflammation in vivo . It was elegantly shown, using complex genetic mouse models, that NEMO has an NF-κB-independent role in protecting epithelial cells in the colon from TNF-mediated RIPK1 kinase-dependent cell death [12]. NEMO deficiency in intestinal epithelial cells (IEC) led to RIPK1 kinase-dependent death and subsequent microbiota-driven colitis [12].…”

Section: The Early Nf-κb-independent Cell Death Checkpointmentioning

confidence: 99%

“…It was elegantly shown, using complex genetic mouse models, that NEMO has an NF-κB-independent role in protecting epithelial cells in the colon from TNF-mediated RIPK1 kinase-dependent cell death [12]. NEMO deficiency in intestinal epithelial cells (IEC) led to RIPK1 kinase-dependent death and subsequent microbiota-driven colitis [12]. The same group also reported an NF-κB-independent role of NEMO in protecting liver parenchymal cells from RIPK1 kinase-mediated apoptosis independently of death receptor activation [56].…”

Section: The Early Nf-κb-independent Cell Death Checkpointmentioning

confidence: 99%

“…This would however render infected cells sensitive to RIPK1 kinase-dependent cell death and thereby facilitate elimination of the infected cells. Furthermore, RIPK1 kinase-dependent cell death has been shown to be inflammatory serving to further alert the immune response [4, 12, 53, 56, 70]. To date, the few concrete examples of a beneficial role for TNF-mediated cytotoxicity in anti-microbial responses are limited to viruses that encode caspase inhibitors and activate necroptosis [71].…”

Section: Physiological Function Of the Early Cell Death Checkpointmentioning

confidence: 99%

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More to Life than NF-κB in TNFR1 Signaling

Ting

Bertrand

2016

Trends in Immunology

219

207

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TNF is a master pro-inflammatory cytokine whose pathogenic role in inflammatory disorders has long been attributed to induction of pro-inflammatory mediators. TNF also activates cell survival and death pathways, and recent studies demonstrated that TNF also causes inflammation by inducing cell death. The default response of most cells to TNF is survival and NF-κB-mediated up-regulation of pro-survival molecules is a well-documented protective mechanism downstream of TNFR1. Recent studies revealed existence of an NF-κB-independent cell death checkpoint that restricts cell demise by inactivating RIPK1. Disruption of this checkpoint leads to RIPK1 kinase-dependent death and causes inflammation in vivo. These revelations bring complexity to the control of TNF-induced cell death, and suggest clinical benefit of RIPK1 inhibitors in TNF-driven human inflammatory disorders.

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“…Extending these studies, it has been recently shown that the NF-κB essential modulator gene prevents intestinal inflammation by inhibiting receptor-interacting protein kinase 1 kinase activity-mediated epithelial cell death, suggesting that inhibition of this kinase could be used in treating patients with NF-κB essential modulator gene mutations [82].…”

Section: Genetic Predisposition Modulates the Microbiota In Intestinamentioning

confidence: 97%

The Microbiome in Visceral Medicine: Inflammatory Bowel Disease, Obesity and Beyond

Chiriac¹,

Mahapatro²,

Becker³

2017

Visc Med

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It has become increasingly evident over the past two decades that the microbiota plays a nurturing role in the development of the immune system. This appears to be important since the amplitude of immune responses has a crucial regulatory function in homeostasis and the prevention of unwanted inflammation. Hence, a malfunctioning gut flora has been shown to play a key role in visceral medicine. Strong evidence demonstrates for example that intestinal inflammation can develop as a result of a dysregulated microbiota, deficient antimicrobial responses, and aberrant bacterial translocation into the bowel wall. In healthy individuals, the bacterial translocation is blocked by a single layer of highly specialized intestinal epithelial cells which forms a strong barrier that lines the gut wall. This structure is responsible for an efficient absorption of nutrients while keeping the luminal flora at bay. In susceptible individuals, for yet incompletely understood reasons, either defective epithelial barrier function or dysregulated microbial composition or microbial pathogens drive intestinal inflammation. Many therapeutic strategies focusing on the modulation of the microbiota have been proposed recently but future research including prospective human studies and gnotobiotic mouse models are still needed to evaluate the contribution and potential therapeutic value of individual bacteria to human health.

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NEMO Prevents RIP Kinase 1-Mediated Epithelial Cell Death and Chronic Intestinal Inflammation by NF-κB-Dependent and -Independent Functions

Cited by 167 publications

References 37 publications

Novel insights into microbiome in colitis and colorectal cancer

Novel insights into microbiome in colitis and colorectal cancer

More to Life than NF-κB in TNFR1 Signaling

The Microbiome in Visceral Medicine: Inflammatory Bowel Disease, Obesity and Beyond

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