Brain endothelial cells as phagocytes: mechanisms and implications

Brain microvascular endothelial cells (BECs) lining the brain capillaries form the anatomical site of the blood-brain barrier (BBB), providing a highly selective barrier to support brain homeostasis and function. While the BBB acts as a barrier to immune cells and pathogens under normal conditions, BECs can facilitate their entry into the CNS via a phagocytosis-like mechanism. A similar process is now increasingly reported for a diverse set of cargos, resulting in the categorization of BECs as "non-professional" phagocytes and redefining the conventional view that these cells are functionally non-phagocytic. This review aims to summarize research demonstrating the capacity of BECs to phagocytose various cargos, including aged red blood cells (RBC), myelin debris, and embolic particles. Mechanistically, BEC phagocytosis can be triggered by the exposure of phosphatidylserine on RBC, expression of adhesion molecules such as ICAM-1 and VCAM-1 on BECs, cargo-opsonization, and/or involve BEC cytoskeleton remodeling. Phagocytic activity by BECs has significant clinical implications ranging from regulation of cerebral microvascular patency (particularly by contributing to and resolving capillary stalling), clearance of brain parenchymal debris, and brain parenchymal invasion by pathogens. Further, BEC phagocytosis of RBC, which represents a cell (RBC)-in-cell (BEC) phenomenon, is implicated in hemorrhagic lesions including cerebral microhemorrhages. This review aims to shed light on BEC phagocytosis as an important function within the brain microvascular system and will delve into the underlying mechanisms, discuss the clinical implications, and identify gaps in our understanding of this phenomenon.