Cerebral nitric oxide represses choroid plexus NFκB-dependent gateway activity for leukocyte trafficking.
Chronic neuroinflammation is evident in brain aging and neurodegenerative disorders and is often associated with excessive nitric oxide (NO) production within the central nervous system (CNS). Under such conditions, increased NO levels are observed at the choroid plexus (CP), an epithelial layer that forms the blood-cerebrospinal fluid barrier (BCSFB) and serves as a selective gateway for leukocyte entry to the CNS in homeostasis and following injury. Here, we hypothesized that elevated cerebral NO levels interfere with CP gateway activity. We found that induction of leukocyte trafficking determinants by the CP and sequential leukocyte entry to the CSF are dependent on the CP epithelial NFκB/p65 signaling pathway, which was inhibited upon exposure to NO. Examining the CP in 5XFAD transgenic mouse model of Alzheimer's disease (AD-Tg) revealed impaired ability to mount an NFκB/p65-dependent response. Systemic administration of an NO scavenger in AD-Tg mice alleviated NFκB/p65 suppression at the CP and augmented its gateway activity. Together, our findings identify cerebral NO as a negative regulator of CP gateway activity for immune cell trafficking to the CNS.
Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel kuti.baruch@weizmann.ac.il michal.schwartz@weizmann.ac.il.
Kuti
K
Baruch
Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel.
Alexander
A
Kertser
Department of Biological Services, Weizmann Institute of Science, Rehovot, Israel.
Ziv
Z
Porat
Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel kuti.baruch@weizmann.ac.il michal.schwartz@weizmann.ac.il.
Michal
M
Schwartz
D000544:Alzheimer Disease / Q000235:genetics / Q000276:immunology / Q000473:pathology; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000276:immunology; D001921:Brain / Q000378:metabolism*; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D002831:Choroid Plexus / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D007962:Leukocytes / Q000187:drug effects* / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism* / Q000494:pharmacology*
D016328:NF-kappa B; D009569:Nitric Oxide
BCSFB; NFκB; choroid plexus; nitric oxide