An epithelial Nfkb2 pathway exacerbates intestinal inflammation by supplementing latent RelA dimers to the canonical NF-κB module

Abstract

Aberrant inflammation, such as that associated with inflammatory bowel disease (IBD), is fueled by the inordinate activity of RelA/NF-κB factors. As such, the canonical NF-κB module mediates controlled nuclear activation of RelA dimers from the latent cytoplasmic complexes. What provokes pathological RelA activity in the colitogenic gut remains unclear. The noncanonical NF-κB pathway typically promotes immune organogenesis involving Nfkb2 gene products. Because NF-κB pathways are intertwined, we asked whether noncanonical signaling aggravated inflammatory RelA activity. Our investigation revealed frequent engagement of the noncanonical pathway in human IBD. In a mouse model of experimental colitis, we established that Nfkb2-mediated regulations escalated the RelA-driven proinflammatory gene response in intestinal epithelial cells, exacerbating the infiltration of inflammatory cells and colon pathologies. Our mechanistic studies clarified that cell-autonomous Nfkb2 signaling supplemented latent NF-κB dimers, leading to a hyperactive canonical RelA response in the inflamed colon. In sum, the regulation of latent NF-κB dimers appears to link noncanonical Nfkb2 signaling to RelA-driven inflammatory pathologies and may provide for therapeutic targets.

NF-κB Inducing Kinase Regulates Intestinal Immunity and Homeostasis

“…However, p100 also dimerizes with RelB as a precursor of non-canonical NF-κB ( 69 ), which is utilized by the NIK signaling downstream of LTβR, preventing the inhibitory effect of p100 as well as enhancing the non-canonical NF-κB signaling and finally forming a positive loop to maintain proinflammatory responses to counter bacteria ( 67 ). In agreement with previous findings, a recent publication reported that non-canonical NF-κB signaling enhanced canonical RelA mediated inflammatory responses in IECs and exacerbated colitis ( 70 ). They also revealed an upregulated non-canonical NF-κB signaling in IBD patients, indicating that uncontrolled IEC-specific NIK signaling involves in the pathogenesis and progression of IBD ( 70 ).…”

“…In agreement with previous findings, a recent publication reported that non-canonical NF-κB signaling enhanced canonical RelA mediated inflammatory responses in IECs and exacerbated colitis ( 70 ). They also revealed an upregulated non-canonical NF-κB signaling in IBD patients, indicating that uncontrolled IEC-specific NIK signaling involves in the pathogenesis and progression of IBD ( 70 ). In physiological state, intestinal inflammatory response is self-limiting rather than fulminant due to the negative regulatory function of NIK signaling.…”

“…Sustained activation of NIK also shapes microbiome containing high IgA coating bacteria which causes a shift to colitogenic dysbiosis and exacerbate inflammatory responses in patients with UC and CD ( 112 ). Non-canonical NF-κB signaling is reported to enhance canonical RelA mediated inflammatory responses in IECs and exacerbated colitis via crosstalk mechanisms ( 70 ). On the other hand, NIK signaling participates in the maintenance of regulatory microenvironment and intestinal tissue repair.…”

“…revealed that overstimulated NIK induced the fission of mitochondria and cell invasion by regulation of DRP1 phosphorylation in the absence of IKKα and NF-κB, which emerges as a novel mechanism of oncogenesis ( 115 ). Upregulated NIK signaling is also observed in IBD patients ( 70 ). Combined together, these studies provide us with a possible mechanism of inflammation-cancer transition in IBD patients.…”

Origin of the Functional Distinctiveness of NF-κB/p52

“…Yilmaz et al showed that lymphotoxin beta (LTβ), a stimulus of the non-canonical signaling pathway, can induce simultenaous processing of p100 and p105 possibly from the p105/p100 heterocomplexes. In a recent publication, Chawla et al also demonstrated simultaneous processing of p105 and p100 through non-canonical signaling generating p50:RelA and p52:RelA complexes in intestinal epithelial cells ( Chawla et al, 2021 ). Thus, a variety of NF-κB dimers can arise from the processing of p105, p100 and p105/p100 kappaBsomes in a stimulus specific manner.…”