| First Author | Mikuda N | Year | 2020 |
| Journal | J Pathol | Volume | 251 |
| Issue | 2 | Pages | 160-174 |
| PubMed ID | 32222043 | Mgi Jnum | J:292048 |
| Mgi Id | MGI:6447092 | Doi | 10.1002/path.5437 |
| Citation | Mikuda N, et al. (2020) Deficiency in IkappaBalpha in the intestinal epithelium leads to spontaneous inflammation and mediates apoptosis in the gut. J Pathol 251(2):160-174 |
| abstractText | The IkappaB kinase (IKK)-NF-kappaB signaling 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-kappaB signaling, these involve either knockouts of a single family member of NF-kappaB or of upstream kinases that are known to have additional, NF-kappaB-independent, functions. This has made the distinct contribution of NF-kappaB to homeostasis in intestinal epithelium cells difficult to assess. To examine the role of constitutive NF-kappaB activation in intestinal epithelial cells, we generated a mouse model with a tissue-specific knockout of the direct inhibitor of NF-kappaB, Nfkbia/IkappaBalpha. We demonstrate that constitutive activation of NF-kappaB 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 signaling. To determine which NF-kappaB-driven phenotypes are cell-intrinsic, and which are extrinsic and thus require the immune compartment, we established a long-term organoid culture. Constitutive NF-kappaB promoted stem-cell proliferation, mis-localization of Paneth cells, and sensitization 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 signaling 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-kappaB, our findings imply that general anti-inflammatory or immunosuppressive therapies should be supplemented with direct targeting of NF-kappaB within the epithelial compartment in order to attenuate apoptosis, inflammation, and hyperproliferation. (c) 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. |
