Overriding the brain's intrinsic resistance to leukocyte recruitment with intraparenchymal injections of recombinant chemokines.
Following the intracranial injection of lipopolysaccharide or during acute neuronal degeneration, there is a paucity of polymorphonuclear leukocyte recruitment to the brain parenchyma and a delay in monocyte recruitment. The present study investigates whether the injection of specific leukocyte chemoattractants into the murine central nervous system can override this intrinsic resistance. Recombinant alpha-(IL-8/NAP-1 MIP-2, IP-10) and beta-chemokines (MCP-1, RANTES) were injected into the murine hippocampus and leukocyte recruitment was assessed histologically. Injections were also made into the dermis of the hind flank for comparison. At doses of 1 microgram, MCP-1 was found to be the most potent monocyte chemoattractant in the brain parenchyma and skin with IP-10 and RANTES producing minimal monocyte recruitment to both sites. In contrast IL-8, and MIP-2 provoked dramatic polymorphonuclear leukocyte recruitment in both the central nervous system and skin. The polymorphonuclear leukocyte recruitment was associated with a breaching of the blood brain barrier that was particularly severe after MIP-2. Both L-8 and MIP-2 induced blood brain barrier breakdown could be attenuated by prior depletion of the circulating leukocytes. The regulation of polymorphonuclear leukocyte chemoattractants in the brain parenchyma during injury and infection is an important area for future studies.
Bell
M D
MD
Dept of Pharmacology, University of Oxford, U.K.
Taub
D D
DD
Perry
V H
VH
D000818:Animals; D001921:Brain / Q000187:drug effects*; D018932:Chemokine CCL2 / Q000494:pharmacology; D018925:Chemokines / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects*; D007150:Immunohistochemistry; D007278:Injections, Spinal; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D011995:Recombination, Genetic
D018932:Chemokine CCL2; D018925:Chemokines