Endothelial histamine H1 receptor signaling reduces blood-brain barrier permeability and susceptibility to autoimmune encephalomyelitis

Disruption of the blood-brain barrier (BBB) underlies the development of experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis. Environmental factors, such as Bordetella pertussis, are thought to sensitize central endothelium to biogenic amines like histamine, thereby leading to increased BBB permeability. B. pertus-sis-induced histamine sensitization (Bphs) is a monogenic intermediate phenotype of EAE controlled by histamine H-1 receptor (Hrh1/H1R). Here, we transgenically overexpressed H1R in endothelial cells of Hrh1-KO(H1RKO) mice to test the role of endothelial H1R directly in Bphs and EAE. Unexpectedly, transgenic H1RKO mice expressing endothelial H1R under control of the von Willebrand factor promoter (H1RKO-vWF(H1R) Tg) were Bphs-resistant. Moreover, H1RKO-vWF(H1R) Tg mice exhibited decreased BBB permeability and enhanced protection from EAE compared with H1RKO mice. Thus, contrary to prevailing assumptions, our results show that endothelial H1R expression reduces BBB permeability, suggesting that endothelial H1R signaling may be important in the maintenance of cerebrovascular integrity.