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Deficiency in IκBα in the intestinal epithelium leads to spontaneous inflammation and mediates apoptosis in the gut

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Item Type:Article
Title:Deficiency in IκBα in the intestinal epithelium leads to spontaneous inflammation and mediates apoptosis in the gut
Creators Name:Mikuda, N. and Schmidt-Ullrich, R. and Kärgel, E. and Golusda, L. and Wolf, J. and Höpken, U.E. and Scheidereit, C. and Kühl, A.A. and Kolesnichenko, M.
Abstract:The IκB-Kinase (IKK)-NF-κB signalling pathway plays a multifaceted role in inflammatory bowel disease (IBD): on the one hand, it protects from apoptosis; on the other, it activates transcription of numerous inflammatory cytokines and chemokines. Although several murine models of IBD rely on disruption of IKK-NF-κB signalling, these involve either knockouts of a single family-member of NF-κB, or of upstream kinases that are known to have additional, NF-κB-independent, functions. This has made the distinct contribution of NF-κB to homeostasis in intestinal epithelium cells difficult to assess. To examine the role of constitutive NF-κB activation in intestinal epithelial cells, we generated a mouse model with a tissue-specific knockout of the direct inhibitor of NF-κB, Nfkbia/IκBα. We demonstrate that constitutive activation of NF-κB in intestinal epithelial cells induces several hallmarks of IBD including increased apoptosis, mucosal inflammation in both the small intestine and the colon, crypt hyperplasia, and depletion of Paneth cells, concomitant with aberrant Wnt signalling. To determine which NF-κB-driven phenotypes are cell-intrinsic, and which are extrinsic and thus require the immune compartment, we established a long-term organoid culture. Constitutive NF-κB promoted stem-cell proliferation, mis-localisation of Paneth cells, and sensitisation of intestinal epithelial cells to apoptosis in a cell-intrinsic manner. Increased number of stem cells was accompanied by a net increase in Wnt activity in organoids. Because aberrant Wnt signalling is associated with increased risk of cancer in IBD patients and because NFKBIA has recently emerged as a risk locus for IBD, our findings have critical implications for the clinic. In a context of constitutive NF-κB, our findings imply that general anti-inflammatory or immunosuppressive therapies should be supplemented with direct targeting of NF-κB within the epithelial compartment in order to attenuate apoptosis, inflammation, and hyperproliferation.
Keywords:Inflammatory Bowel Disease, Animal Model, NF-κB, Precision Medicine, Inflammation, Intestinal Organoids, Wnt, Stem Cells, Crypts, Animals, Mice
Source:Journal of Pathology
Page Range:160-174
Date:June 2020
Official Publication:https://doi.org/10.1002/path.5437
PubMed:View item in PubMed

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