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  Circadian rhythm disruption impairs tissue homeostasis and exacerbates chronic inflammation in the intestine

Pagel, R., Bär, F., Schröder, T., Sünderhauf, A., Künstner, A., Ibrahim, S. M., et al. (2017). Circadian rhythm disruption impairs tissue homeostasis and exacerbates chronic inflammation in the intestine. The FASEB Journal, 31(11), 4707-4719. doi:10.1096/fj.201700141RR.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-002E-8BF6-F Version Permalink: http://hdl.handle.net/21.11116/0000-0001-7E68-E
Genre: Journal Article

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 Creators:
Pagel, René, Author
Bär, Florian, Author
Schröder, Torsten, Author
Sünderhauf, Annika, Author
Künstner, Axel1, Author              
Ibrahim, Saleh M., Author
Autenrieth‖, Stella E., Author
Kalies, Kathrin, Author
König, Peter, Author
Tsang, Anthony H., Author
Bettenworth, Dominik, Author
Divanovic, Senad, Author
Lehnert, Hendrik, Author
Fellermann, Klaus, Author
Oster, Henrik, Author
Derer, Stefanie, Author
Sina, Christian, Author
Affiliations:
1Guest Group Evolutionary Genomics, Max Planck Institute for Evolutionary Biology, Max Planck Society, ou_1445638              

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Free keywords: epithelial cells; necroptosis; inflammatory bowel disease; bowel-disease; ulcerative-colitis; crohns-disease; cell-differentiation; sleep disturbances; in-vivo; clock; genes; mper2; mice; Biochemistry & Molecular Biology; Life Sciences & Biomedicine
 Abstract: Endogenous circadian clocks regulate 24-h rhythms of physiology and behavior. Circadian rhythm disruption (CRD) is suggested as a risk factor for inflammatory bowel disease. However, the underlying molecular mechanisms remain unknown. Intestinal biopsies from Per1/2 mutant and wild-type (WT) mice were investigated by electron microscopy, immunohistochemistry, and bromodeoxyuridine pulse-chase experiments. TNF-alpha was injected intraperitoneally, with or without necrostatin-1, into Per1/2 mice or rhythmic and externally desynchronized WT mice to study intestinal epithelial cell death. Experimental chronic colitis was induced by oral administration of dextran sodium sulfate. In vitro, caspase activity was assayed in Per1/2-specific small interfering RNA-transfected cells. Wee1 was overexpressed to study antiapoptosis and the cell cycle. Genetic ablation of circadian clock function or environmental CRD in mice increased susceptibility to severe intestinal inflammation and epithelial dysregulation, accompanied by excessive necroptotic cell death and a reduced number of secretory epithelial cells. Receptor-interacting serine/threonine-protein kinase (RIP)-3-mediated intestinal necroptosis was linked to increased mitotic cell cycle arrest via Per1/2-controlled Wee1, resulting in increased antiapoptosis via cellular inhibitor of apoptosis-2. Together, our data suggest that circadian rhythm stability is pivotal for the maintenance of mucosal barrier function. CRD increases intestinal necroptosis, thus rendering the gut epithelium more susceptible to inflammatory processes.

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Language(s): eng - English
 Dates: 2017-02-172017-06-272017-07-142017-11
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Method: -
 Identifiers: DOI: 10.1096/fj.201700141RR
 Degree: -

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Title: The FASEB Journal
  Other : FASEB J.
Source Genre: Journal
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Publ. Info: Bethesda, Md. : The Federation
Pages: 4707-4719 Volume / Issue: 31 (11) Sequence Number: - Start / End Page: 4707 - 4719 Identifier: ISSN: 0892-6638
CoNE: /journals/resource/954927535970_1