| dc.description.abstract | Central nervous system (CNS) immune privilege is imparted by a complex set of mechanisms designed to protect the fragile brain tissue. Brain endothelial cells (BECs), the main functional unit of the blood-brain barrier (BBB), play an important role in maintaining CNS homeostasis. BECs are equipped with specialized molecular machinery that facilitates tight regulation of solute exchange between peripheral circulation and CNS. In addition to maintaining an optimal chemical environment, BECs also play an essential role in regulating entry of leukocytes into the CNS, thus contributing to immune privilege. BECs express low levels of leukocyte receptors that withhold passive entry of leukocytes into the CNS. It is well established that, unlike peripheral endothelial cells, BECs are resilient to mild inflammatory stimuli and do not rapidly upregulate expression of inflammatory signatures. However, the molecular mediators governing this phenotype are unclear. Using human pluripotent stem-cell derived models, we identified IQGAP2, a scaffold protein, as a potential regulator of BEC mechanisms. In the absence of Iqgap2, mouse BECs exhibit a profound inflammatory signature, including extensive upregulation of adhesion receptors and antigen-processing machinery. Additionally, loss of Iqgap2 increased infiltration of peripheral leukocytes into the brain in multiple animal models. Overall, these results implicate IQGAP2 as an essential regulator of BBB-mediated CNS immune privilege. | |
