IQGAP2 regulates blood-brain barrier immune dynamics

Abstract

AbstractBrain endothelial cells (BECs) play an important role in maintaining central nervous system (CNS) homeostasis through blood-brain barrier (BBB) functions. In addition to actively regulating material exchange between the circulation and CNS, BECs express low baseline levels of adhesion receptors, which limits entry of leukocytes. Supporting cells in the neurovascular unit, such as astrocytes and pericytes, are crucial for promoting this immune privilege phenotype in BECs. However, the molecular mediators governing this phenotype are unclear. Here, we explored how BBB immune privilege is influenced by IQGAP2, a scaffold protein associated with elevated barrier function. Using single-cell RNA sequencing and immunohistology, we show that BECs from mice lacking Iqgap2 exhibit a profound inflammatory signature, including extensive upregulation of adhesion receptors and antigen-processing machinery. Further, in zebrafish and mice, loss of Iqgap2 increases infiltration of peripheral leukocytes into the brain. Overall, our results implicate IQGAP2 as an essential regulator of BBB immune privilege.