Detachment of Brain Pericytes from the Basal Lamina is Involved in Disruption of the Blood–Brain Barrier Caused by Lipopolysaccharide-Induced Sepsis in Mice
- 1.2k Downloads
The blood–brain barrier (BBB) is highly restrictive of the transport of substances between blood and the central nervous system. Brain pericytes are one of the important cellular constituents of the BBB and are multifunctional, polymorphic cells that lie within the microvessel basal lamina. The present study aimed to evaluate the role of pericytes in the mediation of BBB disruption using a lipopolysaccharide (LPS)-induced model of septic encephalopathy in mice. ICR mice were injected intraperitoneally with LPS or saline and were sacrificed at 1, 3, 6, and 24 h after injection. Sodium fluorescein accumulated with time in the hippocampus after LPS injection; this hyperpermeability was supported by detecting the extravasation of fibrinogen. Microglia were activated and the number of microglia increased with time after LPS injection. LPS-treated mice exhibited a broken basal lamina and pericyte detachment from the basal lamina at 6–24 h after LPS injection. The disorganization in the pericyte and basal lamina unit was well correlated with increased microglial activation and increased cerebrovascular permeability in LPS-treated mice. These findings suggest that pericyte detachment and microglial activation may be involved in the mediation of BBB disruption due to inflammatory responses in the damaged brain.
KeywordsBlood–brain barrier Brain pericytes Basal lamina Microglia Lipopolysaccharide Inflammation
This work was supported in part by Grants-in-Aid for Scientific Research [(B) 17390159], Grants-in-Aid for Young Scientists [(Start-up) 18890227], Grants-in-Aid for Young Scientists [(B) 19790199] from JSPS, Japan, the Ministry of Health, Labor and Welfare of Japan (H19-nanchi-ippan-006), the Nakatomi Foundation and Research Foundation ITSUU Laboratory. The authors thank Dr. Mária A. Deli (Institute of Biophysics, Biological Research Centre of the Hungarian Academy of Sciences) for pertinent comments on the manuscript and Ms. Hiromi Nakanishi for technical assistance.
- Adams RA, Bauer J, Flick MJ, Sikorski SL, Nuriel T, Lassmann H, Degen JL, Akassoglou K (2007) The fibrin-derived gamma377–395 peptide inhibits microglia activation and suppresses relapsing paralysis in central nervous system autoimmune disease. J Exp Med 204(3):571–582. doi: 10.1084/jem.20061931 PubMedCrossRefGoogle Scholar
- Dohgu S, Takata F, Yamauchi A, Nakagawa S, Egawa T, Naito M, Tsuruo T, Sawada Y, Niwa M, Kataoka Y (2005) Brain pericytes contribute to the induction and up-regulation of blood-brain barrier functions through transforming growth factor-beta production. Brain Res 1038:208–215. doi: 10.1016/j.brainres.2005.01.027 PubMedCrossRefGoogle Scholar
- Paxinos G, Franklin KBJ (2001) The mouse brain in stereotaxic coordinates. Academic Press, San DiegoGoogle Scholar
- Semmler A, Frisch C, Debeir T, Ramanathan M, Okulla T, Klockgether T, Heneka MT (2007) Long-term cognitive impairment, neuronal loss and reduced cortical cholinergic innervation after recovery from sepsis in a rodent model. Exp Neurol 204(2):733–740. doi: 10.1016/j.expneurol.2007.01.003 PubMedCrossRefGoogle Scholar
- Takata F, Dohgu S, Yamauchi A, Sumi N, Nakagawa S, Naito M, Tsuruo T, Shuto H, Kataoka Y (2007) Inhibition of transforming growth factor-beta production in brain pericytes contributes to cyclosporin A-induced dysfunction of the blood-brain barrier. Cell Mol Neurobiol 27(3):317–328. doi: 10.1007/s10571-006-9125-x PubMedCrossRefGoogle Scholar