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

Abstract

The IκB kinase (IKK)–NF‐κB 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‐κB signaling, 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 signaling. 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‐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‐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. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Plasticity of Paneth cells and their ability to regulate intestinal stem cells

“…In addition, the IκB kinase (IKK)-NF-κB signalling pathway is involved in inflammatory process when its activation caused the depletion of PCs [ 121 ]. Furthermore, STAT5-dependent JAK2 signalling and JAK1-dependent STAT1 signalling are required for anti-inflammatory cytokine; the absence of STAT5 or the activation of STAT1 decreases the number of PCs [ 57 , 122 ]. Indoleamine 2,3-dioxygenase 1 (IDO1) was upregulated by inflammatory cytokines, thereby promoting the proliferation of PCs; this process blocks the activation of Notch1 [ 123 ].…”

An epithelialNfkb2pathway exacerbates intestinal inflammation by supplementing latent RelA dimers to the canonical NF-κB module

“…Pro-inflammatory gene activation by NF-κB factors in IECs represents a key event in the initiation of colitis (Friedrich et al, 2019; Mikuda et al, 2020). We performed RNA-seq analyses to address if the Nfkb2 pathway tuned the transcriptional response of IECs in the colitogenic gut (STAR ✪ METHODS).…”

“…Previous mouse studies revealed a rather complex role of the canonical pathway in the colon (Wullaert et al, 2011; Zaidi and Wine, 2018). Genetic deficiency of the inhibitory IκBα in IECs caused spontaneous intestinal inflammation (Mikuda et al, 2020). However, a complete lack of canonical signaling in IEC-specific knockouts of RelA or IKK2 sensitized those mice to experimental colitis despite reduced inflammatory gene activation (Eckmann et al, 2008; Steinbrecher et al, 2008).…”

Transcriptional repression of NFKBIA triggers constitutive IKK‐ and proteasome‐independent p65/RelA activation in senescence

“…We next asked whether in vivo, constitutive NF-jB resulting from a knockout of Nfkbia would also trigger SASP, but not senescence-associated proliferative arrest. Since ubiquitous loss of IjBa causes early postnatal lethality (Beg et al, 1995;Klement et al, 1996), we generated intestinal epithelium-restricted (villin-Cre × floxed Nfkbia) knockout mice (Mikuda et al, 2020). Importantly, we observed hyperproliferation of cells, leading to crypt hyperplasia and enrichment of genes responsible for cell cycle progression.…”