Bibliographic Details
| Title: |
CCL2 upregulation triggers hypoxic preconditioning-induced protection from stroke |
| Authors: |
Stowe Ann M, Wacker Bradley K, Cravens Petra D, Perfater Jennifer L, Li Min K, Hu Ruilong, Freie Angela B, Stüve Olaf, Gidday Jeffrey M |
| Source: |
Journal of Neuroinflammation, Vol 9, Iss 1, p 33 (2012) |
| Publisher Information: |
BMC, 2012. |
| Publication Year: |
2012 |
| Collection: |
LCC:Neurology. Diseases of the nervous system |
| Subject Terms: |
Neurology. Diseases of the nervous system, RC346-429 |
| More Details: |
Abstract Background A brief exposure to systemic hypoxia (i.e., hypoxic preconditioning; HPC) prior to transient middle cerebral artery occlusion (tMCAo) reduces infarct volume, blood-brain barrier disruption, and leukocyte migration. CCL2 (MCP-1), typically regarded as a leukocyte-derived pro-inflammatory chemokine, can also be directly upregulated by hypoxia-induced transcription. We hypothesized that such a hypoxia-induced upregulation of CCL2 is required for HPC-induced ischemic tolerance. Methods Adult male SW/ND4, CCL2-null, and wild-type mice were used in these studies. Cortical CCL2/CCR2 message, protein, and cell-type specific immunoreactivity were determined following HPC (4 h, 8% O2) or room air control (21% O2) from 6 h through 2 weeks following HPC. Circulating leukocyte subsets were determined by multi-parameter flow cytometry in naïve mice and 12 h after HPC. CCL2-null and wild-type mice were exposed to HPC 2 days prior to tMCAo, with immunoneutralization of CCL2 during HPC achieved by a monoclonal CCL2 antibody. Results Cortical CCL2 mRNA and protein expression peaked at 12 h after HPC (both p < 0.01), predominantly in cortical neurons, and returned to baseline by 2 days. A delayed cerebral endothelial CCL2 message expression (p < 0.05) occurred 2 days after HPC. The levels of circulating monocytes (p < 0.0001), T lymphocytes (p < 0.0001), and granulocytes were decreased 12 h after HPC, and those of B lymphocytes were increased (p < 0.0001), but the magnitude of these respective changes did not differ between wild-type and CCL2-null mice. HPC did decrease the number of circulating CCR2+ monocytes (p < 0.0001) in a CCL2-dependent manner, but immunohistochemical analyses at this 12 h timepoint indicated that this leukocyte subpopulation did not move into the CNS. While HPC reduced infarct volumes by 27% (p < 0.01) in wild-type mice, CCL2-null mice subjected to tMCAo were not protected by HPC. Moreover, administration of a CCL2 immunoneutralizing antibody prior to HPC completely blocked (p < 0.0001 vs. HPC-treated mice) the development of ischemic tolerance. Conclusions The early expression of CCL2 in neurons, the delayed expression of CCL2 in cerebral endothelial cells, and CCL2-mediated actions on circulating CCR2+ monocytes, appear to be required to establish ischemic tolerance to focal stroke in response to HPC, and thus represent a novel role for this chemokine in endogenous neurovascular protection. |
| Document Type: |
article |
| File Description: |
electronic resource |
| Language: |
English |
| ISSN: |
1742-2094 |
| Relation: |
http://www.jneuroinflammation.com/content/9/1/33; https://doaj.org/toc/1742-2094 |
| DOI: |
10.1186/1742-2094-9-33 |
| Access URL: |
https://doaj.org/article/bffb7e7368d34415bc8bb743c689246f |
| Accession Number: |
edsdoj.bffb7e7368d34415bc8bb743c689246f |
| Database: |
Directory of Open Access Journals |
