Intestinal Inflammation and Dysregulated Immunity in Patients With Inherited Caspase-8 Deficiency

Lehle, Anna S.; Farin, Henner F.; Marquardt, Benjamin; Michels, Birgitta E.; Magg, Thomas; Li, Yue; Liu, Yanshan; Ghalandary, Maryam; Lammens, Katja; Hollizeck, Sebastian; Rohlfs, Meino; Hauck, Fabian; Conca, Raffaele; Walz, Christoph; Weiss, Batia; Lev, Atar; Simon, Amos J.; Groß, Olaf; Gaidt, Moritz M.; Hornung, Veit; Clevers, Hans; Yazbeck, Nadine; Hanna-Wakim, Rima; Shouval, Dror S.; Warner, Neil; Somech, Raz; Muise, Aleixo M.; Snapper, Scott B.; Bufler, Philip; Koletzko, Sibylle; Klein, Christoph; Kotlarz, Daniel

doi:10.1053/j.gastro.2018.09.041

Cited by 96 publications

(75 citation statements)

References 12 publications

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“…It will therefore be of great interest to mechanistically tease apart these novel pathways, and ascertain their role, particularly specific BAX/BAK activation, in metabolic and common inflammatory diseases. It is worth mentioning that genetic loss or mutation of death receptor and TLR signaling machinery, including XIAP, A20, LUBAC components HOIL and HOIP and most recently RIPK1 and caspase‐8, have all been linked to pathogen molecule‐associated hyperinflammation linked to NLRP3 and IL‐1β activation . A consensus on a universal event required to trigger NLRP3 activation to diverse activators also remains elusive.…”

Section: Discussionmentioning

confidence: 99%

Stressing out the mitochondria: Mechanistic insights into NLRP3 inflammasome activation

Yabal

Calleja

Simpson

et al. 2018

Journal of Leukocyte Biology

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Inflammasomes are multimeric protein complexes that induce the cleavage and release of bioactive IL-1 and cause a lytic form of cell death, termed pyroptosis. Due to its diverse triggers, ranging from infectious pathogens and host danger molecules to environmental irritants, the NOD-like receptor protein 3 (NLRP3) inflammasome remains the most widely studied inflammasome to date. Despite intense scrutiny, a universal mechanism for its activation remains elusive, although, recent research has focused on mitochondrial dysfunction or potassium (K + ) efflux as key events. In this review, we give a general overview of NLRP3 inflammasome activation and explore the recently emerging noncanonical and alternative pathways to NLRP3 activation. We highlight the role of the NLRP3 inflammasome in the pathogenesis of metabolic disease that is associated with mitochondrial and oxidative stress. Finally, we interrogate the mechanisms proposed to trigger NLRP3 inflammasome assembly and activation. A greater understanding of how NLRP3 inflammasome activation is triggered may reveal new therapeutic targets for the treatment of inflammatory disease. K E Y W O R D Scaspases, inflammasome, metabolism, mitochondria, reactive oxygen species Abbreviations: AIM2, absent in Melanoma; AMPK, AMP-activated protein kinase; APAF-1, apoptosis protease activating factor-1; ASC, apoptosis-associated speck-like protein containing a caspase recruitment domain; BMDCs, bone marrow dendritic

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Section: Discussionmentioning

confidence: 99%

Stressing out the mitochondria: Mechanistic insights into NLRP3 inflammasome activation

Yabal

Calleja

Simpson

et al. 2018

Journal of Leukocyte Biology

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“…In the intestinal epithelia, the brake is provided by the effector caspase drICE, halting unwanted inflammatory responses. Caspase-8-mediated cleavage of RIPK1 is essential to suppress inflammation in mammals and loss-of caspase-8 has been associated with immunodeficiency or early onset inflammatory bowel disease in humans (Newton, 2020, Lehle at al., 2019, Chun et al, 2002. We report, a similar caspase-mediated regulatory step, suppressing spontaneous inflammation in the form of drICE-mediated cleavage of DIAP2.…”

Section: Discussionmentioning

confidence: 99%

drICE restrains DIAP2-mediated inflammatory signalling and intestinal inflammation

Kietz

Pollari

Tuominen

et al. 2020

Preprint

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AbstractThe Drosophila IAP protein, DIAP2, is a key mediator of NF-κB signalling and is required for immune activation, both locally in the intestinal epithelia and during systemic, fat body-induced responses. We have found that transgenic expression of DIAP2 induces inflammation in the intestine, but not in the fat body, indicating a need for regulating DIAP2 in microbiotic environments. We describe the Drosophila caspase drICE, a known interaction partner of DIAP2, as a regulator of DIAP2 and NF-κB signalling in the intestinal epithelium. drICE acts by cleaving, and interfering with DIAP2’s ability to ubiquitinate and, thereby, activate mediators of the NF-κB pathway. The drICE-cleaved form of DIAP2 is, moreover, unable to induce inflammation during basal conditions in the intestine. Interestingly, cleavage of DIAP2 does not interfere with pathogen-induced signalling, suggesting that drICE protects from immune responses induced by resident microbes. Accordingly, the negative regulatory effect of drICE is lost when rearing flies axenic. Hence, we show that drICE halts unwanted inflammatory signalling in the intestine by forming an inhibitory complex with DIAP2, interfering with the ability of DIAP2 to induce downstream signalling and NF-κB target gene activation.

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“…Interestingly, glucocorticoids and tofacitinib, in current use in IBD, prevented Paneth cell death. Recently, it was described that also patients with inherited caspase-8 deficiency may develop intestinal inflammation but the role of caspase 8-genetics in Crohn's disease is not fully established (90).…”

Section: The Paneth Cell and Non-genetic Links To Crohn's Diseasementioning

confidence: 99%

An Update Review on the Paneth Cell as Key to Ileal Crohn's Disease

Wehkamp

Stange

2020

Front. Immunol.

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The Paneth cells reside in the small intestine at the bottom of the crypts of Lieberkühn, intermingled with stem cells, and provide a niche for their neighbors by secreting growth and Wnt-factors as well as different antimicrobial peptides including defensins, lysozyme and others. The most abundant are the human Paneth cell α-defensin 5 and 6 that keep the crypt sterile and control the local microbiome. In ileal Crohn's disease various mechanisms including established genetic risk factors contribute to defects in the production and ordered secretion of these peptides. In addition, lifestyle risk factors for Crohn's disease like tobacco smoking also impact on Paneth cell function. Taken together, current evidence suggest that defective Paneth cells may play the key role in initiating inflammation in ileal, and maybe ileocecal, Crohn's disease by allowing bacterial attachment and invasion.

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Intestinal Inflammation and Dysregulated Immunity in Patients With Inherited Caspase-8 Deficiency

Cited by 96 publications

References 12 publications

Stressing out the mitochondria: Mechanistic insights into NLRP3 inflammasome activation

Stressing out the mitochondria: Mechanistic insights into NLRP3 inflammasome activation

drICE restrains DIAP2-mediated inflammatory signalling and intestinal inflammation

An Update Review on the Paneth Cell as Key to Ileal Crohn's Disease

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