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. pertussis-induced histamine sensitization (Bphs) is a monogenic intermediate phenotype of EAE controlled by histamine H₁ 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-vWFH¹R Tg) were Bphs-resistant. Moreover, H₁RKO-vWFH¹R 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.