A noncanonical NF-kB - ?-catenin signaling axis in dendritic cells instructs gut inflammation

Abstract Dendritic cells (DCs) balance intestinal homeostasis against inflammatory insults. In particular, the noncanonical NF-kB pathway, which activates RelB:p52 heterodimers, has been implicated in DC differentiation. However, if DC-intrinsic noncanonical signaling modulates DC function in the inflamed gut remains unclear. Here we report that genetic ablation of the noncanonical signaling in DCs accumulated regulatory T cells in the lamina propria and associated lymph nodes, restraining inflammation in the colitogenic gut. Our mechanistic investigation revealed that an impaired RelB:p52 gene function, rather unexpectedly, augmented the abundance of active β-catenin via impairment of the β-catenin destruction complex. In turn, β-catenin transcriptionally upregulated Raldh2, imparting a retinoic acid gene signature and tolerogenic functions to noncanonical NF-kB-deficient DCs. Indeed, mice possessing DC-intrinsic noncanonical signaling defects exhibited an increased frequency of β-catenin +DCs in the gut and resilience to chemical induced experimental colitis. Taken together, we chart a novel crosstalk between noncanonical NF-kB signaling and the β-catenin pathway that instructs tolerogenic DC functions and modulates inflammation in the gut. National Institute of Immunology Core funding and BT/PR36631/BRB/10/1862/2020, Department of Biotechnology (DBT).