R-spondin driven NF-κB signaling shapes the gastric gland base cell compartment and enables rapid inflammation upon infection of stem cells

Mechanisms by which mucosal surfaces discriminate between harmless bacteria and pathogens are not well understood. Gastric gland base colonization by Helicobacter pylori, in contrast to surface colonization causes inflammation and gastric pathology. This compartment contains stem cells, that are controlled by stromal R-spondin 3. Here, we asked how R-spondin 3 and its receptors Lgr4 and Lgr5 control inflammatory responses to H. pylori. We find that epithelial responses to infection are mediated by Rspodnin 3 mainly via Lgr4, causing NF-κB signaling and pro-inflammatory chemokine production. R-spondin 3 signaling induces a baseline NF-κB activity exclusively in the gland base, enabling rapid nuclear translocation of p65 upon infection, triggering inflammtion. Intriguingly, knockout mice that lack NF-κB signaling display an almost complete loss of gland base cells. Our data reveal that gland base cells are primed to act as central proinflammatory mediators, enabling rapid and selective mucosal responses to infections. Microarray experiments were performed as dual-color hybridizations on Agilent whole mouse catalog 4x44K (Agilent-014868) arrays. To compensate for dye-specific effects, a dye-reversal color-swap was applied. We here investigated the function of Lgr4 and Lgr5, R-spondin 3 receptors, by using conditional mouse models that enable manipulation of Lgr4 and Lgr5 gene expression in gastric Axin2+ cells. The effect and the physiological function of Lgr4 was analzyed in the antrum with Lgr4 gene knock-out mice (Lgr4fl/fl/Axin2CreErt2). These mice were infected for 2 month with Helicobacter pylori. In addition the effect and physiological function of Lgr4 and Lgr5 was analyzed in the antrum with Lgr4 and Lgr5 gene knock-out mice (Lgr4fl/flLgr5fl/flAxin2CreErt2).