MCP-1/CCR-2-double-deficiency severely impairs the migration of hematogenous inflammatory cells following transient cerebral ischemia in mice

• Published in: Experimental neurology Vol. 233; no. 2; pp. 849 - 858
• Main Authors: Schuette-Nuetgen, Katharina, Strecker, Jan-Kolja, Minnerup, Jens, Ringelstein, E. Bernd, Schilling, Matthias
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 01.02.2012; Elsevier
• Subjects: Animals; Biological and medical sciences; CC chemokine (CCR)-2; Cerebral ischemia; Chemokine CCL2 - deficiency; Double deficient bone marrow chimeras; Green fluorescent protein (GFP) transgenic mice; Inflammation - genetics; Inflammation - metabolism; Inflammation - pathology; Inflammation Mediators - physiology; Ischemic Attack, Transient - genetics; Ischemic Attack, Transient - metabolism; Ischemic Attack, Transient - pathology; Macrophages - metabolism; Macrophages - pathology; Male; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Microglia - metabolism; Microglia - pathology; Monocyte chemoattractant protein-1 (MCP-1); Neurology; Neutrophil Infiltration - genetics; Receptors, CCR2 - deficiency; Severity of Illness Index; Vascular diseases and vascular malformations of the nervous system; Double deficient bone marrow chimeras; Cerebral ischemia; Green fluorescent protein (GFP) transgenic mice; CC chemokine (CCR)-2; Monocyte chemoattractant protein-1 (MCP-1); Nervous system diseases; Monocyte; Deficiency; Rodentia; Cardiovascular disease; CC chemokine; Cerebral disorder; Transients; Vascular disease; Cell motility; Vertebrata; Mammalia; Mouse; Animal; Central nervous system disease; Green fluorescent protein; Brain ischemia; Bone marrow; Cerebrovascular disease
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1016/j.expneurol.2011.12.011

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 7days following focal cerebral ischemia. This argues for a 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-1α, 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 receptor 5 (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. ► Investigation of MCP-1/CCR-2-double deficient mice in cerebral ischemia. ► Recruitment of inflammatory cells was virtually entirely abrogated in the ischemic brain. ► MCP-1/CCR-2 axis plays a predominant role in chemotaxis of monocytes. ► Chemokine analysis revealed a reduced, delayed or lack of relevant compensatory response in MCP-1−/−/CCR-2−/−-mice. ► Only CCR-5 rose above wildtype levels in MCP-1−/−/CCR-2−/−-animals and might explain increased microglial activation.