Regulation of monocyte cell fate by blood vessels through Notch signaling and significance for vascular repair
Final Report Abstract
Monocytes play important role in protection from infections and injury, but are also implicated in onset and progression of major inflammatory diseases, including, cardiovascular, neurodegenerative and kidney diseases, cancer, autoimmunity and diabetes. To understand the pathogenesis of these diseases and identify potential new targets for therapy, study of monocyte origin, differentiation and their function is crucial. Despite advances in monocyte biology, these questions remain incompletely understood and are the subject of current research. We studied the mechanisms governing monocyte cell fate and analyzed monocyte response in a model of TLR7-induced inflammation. We found, that DLL1-Notch2 and TLR7-Myd88 pathways independently and synergistically promote monocyte conversion and drive Ly6Clo patrolling monocyte development from conventional Ly6Chi monocytes under inflammatory conditions. In opposite, TLR7 stimulation in the absence of Notch2 induce ectopic differentiation of Ly6Chi monocytes into macrophages and dendritic cells, which infiltrate the spleen and major blood vessels and are accompanied by aberrant systemic inflammation. We found that patrolling monocytes facilitate endothelial regeneration after vascular injury. This process was independent of Notch2 under inflammatory conditions and could be attributable to macrophages, which expand and infiltrate blood vessels. Together, these results build solid background for our new studies, which now aim to address the origin and the function of Notch-regulated macrophages in vascular inflammation and subsequent organ damage. We have shown that monocytes possess organ-specific characteristics - splenic ones being more mature and prone to rapid differentiation in opposite to bone marrow counterparts. While spleen plays the role of reservoir and is dispensable for monocyte conversion, observing organ-specific differences in monocytes was unexpected. Now, it remains to prove, whether such difference also exist in other organs and how is this regulated. Lastly, our extended studies of human monocytes aimed to generate in vitro culture system of monocyte conversion. We found that CD14+ conventional monocytes isolated from peripheral blood differentiate independent of Notch and obtain phenotype of patrolling monocytes only partially. Now, further efforts employing bone marrow monocytes and improved culture conditions are necessary to develop successful in vitro culture system for subsequent studies of monocyte biology and for potential therapeutic applications.
Publications
- Notch and TLR signaling coordinate monocyte cell fate and inflammation. Elife. 2020 Jul 29;9:e57007
Gamrekelashvili J, Kapanadze T, Sablotny S, Ratiu C, Dastagir K, Lochner M, Karbach S, Wenzel P, Sitnow A, Fleig S, Kalinke U, Haller H, Holzmann B, Limbourg FP
(See online at https://doi.org/10.7554/elife.57007) - Analysis of monocyte cell fate by adoptive transfer in a murine model of TLR7-induced systemic inflammation. Bio Protoc. 2021 May 5;11(9):e4007
Gamrekelashvili J, Haller H, Limbourg FP
(See online at https://doi.org/10.21769/bioprotoc.4007)
