TY - JOUR
T1 - Endothelial histamine H1 receptor signaling reduces blood-brain barrier permeability and susceptibility to autoimmune encephalomyelitis
AU - Lu, Changming
AU - Diehl, Sean A.
AU - Noubade, Rajkumar
AU - Ledoux, Jonathan
AU - Nelson, Mark T.
AU - Spach, Karen
AU - Zachary, James F.
AU - Blankenhorn, Elizabeth P.
AU - Teuscher, Cory
N1 - AI041747, NIAID NIH HHS, United StatesAI045666, NIAID NIH HHS, United StatesAI058052, NIAID NIH HHS, United StatesHL089243, NHLBI NIH HHS, United StatesHL44455, NHLBI NIH HHS, United StatesNS036526, NINDS NIH HHS, United StatesNS060901, NINDS NIH HHS, United StatesNS061014, NINDS NIH HHS, United StatesNS069628, NINDS NIH HHS, United States
PY - 2010/11/2
Y1 - 2010/11/2
N2 - Disruption of the blood-brain barrier (BBB) underlies the development of experimental autoimmune encephalomyelitis (EAE)andmultiple 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 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 H 1R under control of the von Willebrand factor promoter (H 1RKO-vWFH1R Tg) were Bphs-resistant. Moreover, H 1RKO-vWFH1R Tg mice exhibited decreased BBB permeability and enhanced protection from EAE comparedwith H1RKO mice. Thus, contrary to prevailing assumptions, our results show that endothelial H 1R expression reduces BBB permeability, suggesting that endothelial H1R signaling may be important in the maintenance of cerebrovascular integrity.
AB - Disruption of the blood-brain barrier (BBB) underlies the development of experimental autoimmune encephalomyelitis (EAE)andmultiple 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 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 H 1R under control of the von Willebrand factor promoter (H 1RKO-vWFH1R Tg) were Bphs-resistant. Moreover, H 1RKO-vWFH1R Tg mice exhibited decreased BBB permeability and enhanced protection from EAE comparedwith H1RKO mice. Thus, contrary to prevailing assumptions, our results show that endothelial H 1R expression reduces BBB permeability, suggesting that endothelial H1R signaling may be important in the maintenance of cerebrovascular integrity.
KW - Endothelium
KW - Experimental autoimmune encephalomyelitis
KW - Multiple sclerosis
KW - Vascular permeability
KW - Vasoactive amine sensitization
UR - https://www.scopus.com/pages/publications/78650480308
U2 - 10.1073/pnas.1008816107
DO - 10.1073/pnas.1008816107
M3 - Article
C2 - 20956310
SN - 0027-8424
VL - 107
SP - 18967
EP - 18972
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 44
ER -
