Autoamplification of Notch Signaling in Macrophages by TLR-Induced and RBP-J–Dependent Induction of Jagged1

Several signaling pathways, including the Notch pathway, can modulate TLR activation to achieve responses most appropriate for the environment. One mechanism of TLR-Notch cross-talk is TLR-induced expression of Notch ligands Jagged and Delta that feed back to engage Notch receptors on TLR-activated cells. In this study, we investigated mechanisms by which TLRs induce Notch ligand expression in primary macrophages. TLRs induced Jagged1 expression rapidly and independently of new protein synthesis. Jagged1 induction was augmented by IFN-γ, was partially dependent on canonical TLR-activated NF-κB and MAPK signaling pathways, and elevated Jagged1 expression augmented TLR-induced IL-6 production. Strikingly, TLR-induced Jagged1 expression was strongly dependent on the Notch master transcriptional regulator RBP-J and also on upstream components of the Notch pathway γ-secretase and Notch1 and Notch2 receptors. Thus, Jagged1 is an RBP-J target gene that is activated in a binary manner by TLR and Notch pathways. Early and direct cooperation between TLR and Notch pathways leads to Jagged1-RBP-J-mediated autoamplification of Notch signaling that can modulate later phases of the TLR response.