There is an emerging recognition that the vasculature is not only a conduit for blood flow but actively modulates tissue inflammation and repair by interacting with parenchymal and immune cells. The endothelium serves as the entry point of circulating monocytes transmigrating into the tissue, therefore, endothelial cells (ECs) may modify the downstream the fate of transmigrated monocytes as they differentiate into distinct tissue macrophage phenotypes. Considering the importance of macrophages in the propagation and resolution of inflammation, as well as their roles in tissue repair and regeneration, understanding the interaction between endothelial cells and macrophages may be of great consequence. We will address mechanisms of generation of how vascular endothelial cells instruct macrophages and their role in resolving tissue inflammation. We will specifically focus on fundamental questions such as: What are the EC signals mediating transition to a reparative macrophage phenotype? What signals in macrophages in turn promote the resolution of inflammation and tissue repair? What are the epigenetic and transcriptomic features of these phenotype-shifted macrophages? We will test the hypothesis that the endothelium via Wnt signaling mediates macrophage phenotype transition through modifying mitochondrial metabolism and epigenome that initiates specific transcriptional programs.
In Aim 1, we will define the role of endothelial Wnt signaling in licensing the differentiation of monocytes to pro-resolving macrophages in inflammatory injury. Here we will determine the role of the Wnt signaling regulator Rspondin 3 (Rspo3) derived from ECs in signaling the transition of monocytes to reparative macrophages.
In Aim 2, we will determine the role of metabolic reprogramming and epigenetic modifications of macrophages in mediating phenotype transition and thereby promoting resolution of inflammatory injury.
Endothelial cells line the blood vessels of all organs and can regulate the extent of inflammation and regulate tissue repair in various organs. Macrophages are immune cells which can either enhance or dampen the immune response. The research in this proposal will help us understand how endothelial cells can educate macrophages providing cues and hopefully set the foundation for future treatments that maximize tissue repair during severe inflammation.
