Disruption of Non-canonical NF-κB Signaling in Dendritic Cells Alleviates Intestinal Inflammation by Enhancing the Tolerogenic β-catenin-Raldh2 Axis

Core Concepts

Non-canonical NF-κB signaling in dendritic cells restrains the tolerogenic β-catenin-Raldh2 axis, exacerbating intestinal inflammation.

Abstract

The content examines the role of non-canonical NF-κB signaling in dendritic cells (DCs) in modulating intestinal inflammation. Key highlights:

Experimental colitis in mice is associated with heightened non-canonical NF-κB signaling in intestinal DCs, as evidenced by increased expression of Relb, Nfkb2, and RelB-target genes.

Genetic inactivation of the non-canonical NF-κB pathway in DCs (RelbΔCD11c and Nfkb2ΔCD11c mice) alleviates inflammation in colitogenic mice by improving the frequency of colonic Tregs and IgA+ B cells.

Mechanistically, non-canonical NF-κB signaling restrains the tolerogenic β-catenin-Raldh2 axis in DCs. RelB:p52 upregulates Axin1, which tethers β-catenin to the destruction complex, limiting Raldh2-mediated retinoic acid synthesis.

Introducing β-catenin haploinsufficiency in non-canonical NF-κB-deficient DCs moderates Raldh2 activity and reinstates colitogenic sensitivity in mice.

Intestinal DCs from IBD patients display a deleterious non-canonical NF-κB signature, associated with reduced β-catenin activity and diminished frequencies of Tregs and IgA+ cells.
In summary, the non-canonical NF-κB pathway in DCs subverts the tolerogenic β-catenin-Raldh2 axis, exacerbating intestinal inflammation in experimental colitis and IBD.

Stats

Experimental colitis in mice is associated with a rise in the abundance of Relb and Nfkb2 mRNAs in intestinal DCs.
Genetic inactivation of Relb or Nfkb2 in DCs (RelbΔCD11c and Nfkb2ΔCD11c mice) alleviates bodyweight loss and colon shortening in DSS-induced acute colitis.
Relbfl/fl and RelbΔCD11c mice display a ~2.5-fold increase and ~3.6-fold increase, respectively, in the abundance of β-catenin in intestinal DCs.
Introducing β-catenin haploinsufficiency in RelbΔCD11c mice (Ctnnb1fl/+RelbΔCD11c) restores the frequency of colonic Tregs and fecal sIgA to the levels observed in Relbfl/fl controls.

Quotes

"Non-canonical NF-κB signaling restrains the tolerogenic β-catenin-Raldh2 axis in DCs by upregulating Axin1."
"DC-specific non-canonical NF-κB impairment improved the colonic frequency of Tregs and IgA+ B cells, which fostered luminal IgA and eubiosis."
"A DC defect of non-canonical signaling causes β-catenin-dependent increase in luminal sIgA, fostering the gut microbiome."

Key Insights Distilled From

Non-canonical NF-κB signaling promotes intestinal inflammation by restraining the tolerogenic β-catenin-Raldh2 axis in dendritic cells

by Deka,A., Kum... at www.biorxiv.org 12-05-2023

https://www.biorxiv.org/content/10.1101/2023.12.03.569755v2

Deeper Inquiries

How do environmental or genetic factors trigger the activation of non-canonical NF-κB signaling in intestinal DCs during inflammatory bowel diseases

Environmental and genetic factors can trigger the activation of non-canonical NF-κB signaling in intestinal dendritic cells (DCs) during inflammatory bowel diseases (IBD) through various mechanisms. Environmental factors such as microbial stimuli, inflammatory cytokines, and dietary components can activate signaling pathways that converge on the non-canonical NF-κB pathway in DCs. For example, microbial sensing by DCs can lead to the activation of TNFR superfamily members, including lymphotoxin-β receptor (LTβR), which triggers the non-canonical NF-κB pathway. In the context of IBD, dysbiosis in the gut microbiome can stimulate DCs to engage the non-canonical NF-κB pathway, leading to heightened inflammation.
Genetic factors can also play a role in the activation of non-canonical NF-κB signaling in DCs during IBD. Genetic variations in genes encoding components of the NF-κB pathway, such as RELB and NFKB2, can predispose individuals to aberrant activation of the non-canonical NF-κB pathway in DCs. These genetic alterations may disrupt the balance between pro-inflammatory and tolerogenic signaling in DCs, contributing to the pathogenesis of IBD. Additionally, genetic mutations in regulators of the β-catenin pathway, such as Axin1, can impact the crosstalk between the non-canonical NF-κB and β-catenin pathways in DCs, further exacerbating intestinal inflammation in IBD.

What are the potential therapeutic implications of targeting the non-canonical NF-κB-β-catenin axis in DCs for the management of intestinal inflammation

Targeting the non-canonical NF-κB-β-catenin axis in DCs holds significant therapeutic implications for the management of intestinal inflammation, particularly in the context of IBD. By modulating the activity of the non-canonical NF-κB pathway in DCs, it may be possible to restore the balance between pro-inflammatory and tolerogenic responses in the intestine. Inhibiting non-canonical NF-κB signaling could lead to the upregulation of β-catenin-driven synthesis of retinaldehyde dehydrogenase 2 (Raldh2) in DCs, promoting the production of retinoic acid (RA) and enhancing the tolerogenic properties of DCs.
Therapeutic interventions targeting the non-canonical NF-κB-β-catenin axis in DCs could involve the development of small molecule inhibitors or biologics that specifically modulate the activity of these pathways. By promoting the tolerogenic functions of DCs and enhancing the generation of regulatory T cells (Tregs) and IgA-secreting B cells, such interventions could help to dampen intestinal inflammation and restore gut homeostasis in patients with IBD. Additionally, targeting this axis may have broader implications for the treatment of other inflammatory conditions where dysregulated immune responses play a role.

Given the broader roles of β-catenin and retinoic acid signaling in development and tissue homeostasis, how might the non-canonical NF-κB-mediated regulation of these pathways impact other physiological processes beyond the intestine

The non-canonical NF-κB-mediated regulation of the β-catenin and retinoic acid signaling pathways in intestinal DCs can have significant impacts on other physiological processes beyond the intestine. β-catenin is a key regulator of cell proliferation, differentiation, and tissue homeostasis in various organs and tissues. Dysregulation of the β-catenin pathway has been implicated in cancer, developmental disorders, and other inflammatory conditions. Therefore, the modulation of the non-canonical NF-κB-β-catenin axis in DCs could potentially influence these processes in different tissues and organs.
Similarly, retinoic acid signaling plays a crucial role in immune regulation, development, and metabolism. Beyond its effects on DC function in the intestine, RA is involved in the differentiation of various immune cell subsets, maintenance of epithelial barriers, and modulation of inflammatory responses. Therefore, the non-canonical NF-κB-mediated regulation of the RA pathway in DCs could impact immune responses, tissue repair, and metabolic functions in different physiological contexts. Understanding the broader implications of targeting the non-canonical NF-κB-β-catenin axis in DCs is essential for exploring its therapeutic potential in various disease conditions.