Regulation of monocyte lineage development in systemic and vascular inflammation and the influence of Notch signaling

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Mononuclear-phagocytic system and blood vessels constantly interact with each other to maintain homeostasis. Endothelial cells (EC) provide specific signals and guide classical (Ly6Chi) monocyte differentiation into patrolling (Ly6Clo) monocytes, MHC-II+ monocytes, or macrophages (MF) and dendritic cells (DC). On the other hand, mature phagocytes are implicated in inflammatory reactions and vascular or tissue monitoring. Such versatile EC-to-monocyte cross-talk is impaired by chronic environmental stress, which induces low-grade inflammation and dysregulates monocyte developmental program. This leads to expansion and activation of inflammatory cells, infiltration and subsequent damage of blood vessels and development of cardiovascular disease. Inflammation and vascular pathology is further enhanced when dysregulated phagocytes are exposed to the additional microbial stressors.Ly6Chi monocytes have developmental plasticity for a spectrum of phagocytes as they differentiate into phenotypically and functionally distinct mature cells including Ly6Clo, MHC-II+ monocytes, MF and DCs. This late step of monopoiesis is tightly controlled by EC-to-myeloid Notch signaling. Yet little is known about early steps of monopoiesis, monocyte progenitors and differentiation pathways which define monocyte heterogeneity, developmental plasticity and influence inflammation.We have hypothesized and show in preliminary results that monocytes are derived from at least two independent progenitor lineages, i.e. MDP2- and cMoP-dependent pathways, and this process is controlled by Notch. We developed a new mouse model where Notch2 is specifically deleted in early MDP2-dependent monopoiesis, while the alternative, cMoP-dependent monopoiesis remains intact. Notch2 deletion causes reduction of Ly6Clo- and expansion of MHC-II+ monocytes and DCs in steady state. When subjected to inflammatory stimuli, these mice develop severe inflammation with aberrant expansion of MF-like cells and MHC-II+ monocytes in the blood and MF infiltration of major blood vessels. In vitro Notch ligand DLL1 induced specific expansion of Ly6Clo monocytes, while DLL4 supported MHC-II+ monocyte development. In vivo, downregulation of Dll1 and upregulation of Dll4 in blood vessels with simultaneous expansion of MHC-II+ monocytes, DC and MF during vascular inflammation confirmed ligand-specific regulation of monocyte cell fate. Thus, Notch controls monocyte heterogeneity, differentiation, function and influences inflammation.Here we propose to study pathways of monopoiesis and address the mechanisms of monocyte heterogeneity. We intend to define signaling mechanisms controlling monopoiesis, the function of monocytes and implication for inflammation. This knowledge might be crucial for understanding of the pathophysiology of inflammation and vascular damage and significantly contribute to the design of efficient treatment strategies and preventive measures.