Notch and TLR signaling coordinate monocyte cell fate and inflammation

We studied the role of Notch2 signaling in Ly6Chi monocyte cell fate during TLR7-induced acute inflammation. To characterize the gene expression changes involved in monocyte differentiation, we subjected monocyte subsets from peripheral blood of wt and myeloid Notch2 mutant mice after Sham or IMQ treatment to RNA-sequencing and gene expression analysis. We found that Cell-intrinsic Notch2 and TLR7-Myd88 pathways independently and synergistically promote Ly6Clo patrolling monocyte development from Ly6Chi monocytes under inflammatory conditions. 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 Ly6Chi monocytes into macrophages and dendritic cells. Thus, Notch2 is a master regulator of Ly6Chi monocyte cell fate and inflammation in response to TLR signaling. Overall design: Gene expression analysis of wt or Notch2 mutant monocytes after induction of acute inflammation. Four biological replicates for each experimental condition were analysed; *Hi samples: Ly6Chi (inflammatory) monocytes sorted from the peripheral blood of the sham-treated mice. *Hi+A samples: Ly6Chi (inflammatory) monocytes sorted from the peripheral blood of IMQ- (Imiquimod, Aldara) treated mice. *Lo+A samples: Ly6Clo (patroling) monocytes sorted from the peripheral blood of the IMQ- (Imiquimod, Aldara) treated mice.