<i>Nod2</i> Mutation in Crohn's Disease Potentiates NF-κB Activity and IL-1ß Processing

TLDR

Variants of NOD2 that increase Crohn’s disease susceptibility are thought to impair NF‑κB activation, yet clinical specimens show elevated NF‑κB activity. The study introduced a Crohn’s disease–associated NOD2 variant into the mouse Nod2 locus to investigate its pathophysiological role. The authors generated a knock‑in mouse carrying the disease‑associated NOD2 variant at the endogenous locus. Mutant mice displayed heightened NF‑κB activation and enhanced IL‑1β processing and secretion, leading to greater susceptibility to bacterial‑induced intestinal inflammation and confirming NOD2 as a positive regulator of NF‑κB and IL‑1β.

Abstract

Variants of NOD2, an intracellular sensor of bacteria-derived muramyl dipeptide (MDP), increase susceptibility to Crohn's disease (CD). These variants are thought to be defective in activation of nuclear factor κB (NF-κB) and antibacterial defenses, but CD clinical specimens display elevated NF-κB activity. To illuminate the pathophysiological function of NOD2, we introduced such a variant to the mouse Nod2 locus. Mutant mice exhibited elevated NF-κB activation in response to MDP and more efficient processing and secretion of the cytokine interleukin-1β (IL-1β). These effects are linked to increased susceptibility to bacterial-induced intestinal inflammation and identify NOD2 as a positive regulator of NF-κB activation and IL-1β secretion.