Journal
EXPERIMENTAL NEUROLOGY
Volume 233, Issue 2, Pages 849-858Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.expneurol.2011.12.011
Keywords
Cerebral ischemia; Monocyte chemoattractant protein-1 (MCP-1); CC chemokine (CCR)-2; Double deficient bone marrow chimeras; Green fluorescent protein (GFP) transgenic mice
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Monocyte chemoattractant protein-1 (MCP-1) and its receptor CCR-2 are known to play a major role in inflammatory responses after cerebral ischemia. Mice deficient in either MCP-1 or CCR-2 have been reported to develop smaller infarct sizes and show decreased numbers of infiltrating inflammatory cells. In the present study we used green fluorescent protein (GFP) transgenic mice to investigate the effect of MCP-1/CCR-2-double deficiency on the recruitment of inflammatory cells in a model of both, mild and severe cerebral ischemia. We show that MCP-1/CCR-2-double deficiency virtually entirely abrogates the recruitment of hematogenous macrophages and significantly reduces neutrophil migration to the ischemic brain 4 and 7 days following focal cerebral ischemia. This argues fora predominant role of the MCP-1/CCR-2 axis in chemotaxis of monocytes despite a wide redundancy in the chemokine-receptor-system. Chemokine analysis revealed that even candidates known to be involved in monocyte and neutrophil recruitment like MIP-1 alpha, CXCL-1, C5a, G-CSF and GM-CSF showed a reduced and delayed or even a lack of relevant compensatory response in MCP-1(-/-)/CCR-2(-/-)-mice. Solely, chemokine receptors (CCR-5) increased early in both, but rose above wildtype levels at day 7 in MCP-1(-/-)/CCR-2(-/-)animals, which might explain the higher number of activated microglial cells compared to control mice. Our study was, however, not powered to investigate infarct volumes. Further studies are needed to clarify whether these mechanisms of inflammatory cell recruitment might be essential for early infarct development and final infarct size and to evaluate potential therapeutic implications. (C) 2011 Elsevier Inc. All rights reserved.
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