Notch and TLR signaling coordinate monocyte cell fate and inflammation

Conventional Ly6C hi monocytes have developmental plasticity for a spectrum of differentiated phagocytes. Here we show, using conditional deletion strategies in a mouse model of Toll-like receptor (TLR) 7-induced inflammation, that the spectrum of developmental cell fates of Ly6C hi monocytes, and the resultant inflammation, is coordinately regulated by TLR and Notch signaling. Cell-intrinsic Notch2 and TLR7-Myd88 pathways independently and synergistically promote Ly6C lo patrolling monocyte development from Ly6C hi monocytes under inflammatory conditions, while impairment in either signaling axis impairs Ly6C lo monocyte development. At the same time, TLR7 stimulation in the absence of functional Notch2 signaling promotes resident tissue macrophage gene expression signatures in monocytes and ectopic differentiation of Ly6C hi monocytes into macrophages and dendritic cells, which appear in the blood stream and infiltrate the spleen and major blood vessels, resulting in unrestrained systemic inflammation. Thus, Notch2 is a master regulator of Ly6C hi monocyte cell fate and inflammation in response to TLR signaling.