Chemokine Signals a Way into the Brain

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Science's STKE  04 Nov 2003:
Vol. 2003, Issue 207, pp. tw433-TW433
DOI: 10.1126/stke.2003.207.tw433

Brain endothelial cells, and the tight junctions between them, comprise the blood-brain barrier (BBB), which helps isolate the brain from blood-borne molecules. Various pathological conditions involving inflammation of the central nervous system (CNS) can lead to breakdown of the BBB. During CNS inflammation, monocyte chemoattractant protein-1 (MCP-1) participates in recruiting leukocytes into the CNS. Noting evidence suggesting that CCR2, a receptor for MCP-1, is present on brain endothelial cells, Stamatovic et al. investigated a possible role for MCP-1 and CCR2 in breakdown of the BBB during CNS inflammation. The authors used a combination of reverse-transcription polymerase chain reaction, Western analysis, and immunocytochemistry to show that CCR2 mRNA and protein were present in primary cultures of mouse brain microvascular endothelial cells (mBMECs); both CCR2 mRNA and surface protein were increased after exposure to the proinflammatory cytokine interleukin-1β. MCP-1 decreased transepithelial electrical resistance and increased permeability to inulin across mBMEC monolayers from wild-type mice, but not across mBMEC monolayers from mutant mice that lacked CCR2. MCP-1 elicited rearrangement of the actin cytoskeleton, visible gaps between cells, and redistribution of tight junction proteins. The authors used cDNA microarray analysis together with pharmacological analysis to implicate RhoA and Rho kinase in MCP-1's effects on the cytoskeleton and tight junction permeability, a role substantiated through transfection with a Rho dominant negative mutant, and Western analysis of affinity-precipitated activated Rho. Thus, MCP-1 appears to contribute to breakdown of the BBB during inflammation and may provide a therapeutic target to help limit injury to the CNS during inflammation.

S. M. Stamatovic, R. F. Keep, S. L. Kunkel, A. V. Andjelkovic, Potential role of MCP-1 in endothelial cell tight junction 'opening': Signaling via Rho and Rho kinase. J. Cell Sci. 116, 4615-4628 (2003). [Abstract] [Full Text]

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