Mrp-8 and -14 mediate CNS injury in focal cerebral ischemia |
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Authors: | Gina Ziegler Vincent Prinz Marcus W Albrecht Denise Harhausen Uldus Khojasteh Wolfgang Nacken Matthias Endres Ulrich Dirnagl Wilfried Nietfeld George Trendelenburg |
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Institution: | 1. Max-Planck-Institute for Molecular Genetics, Ihnestr.73, 14195 Berlin, Germany;2. Experimentelle Neurologie, Charité-Universitätsmedizin Berlin, Germany;3. Institute of Immunology, University of Münster, 48129 Münster, Germany;4. Institute for Molecular Virology / ZMBE, 48149 Münster, Germany;5. Center for Stroke Research Berlin, Charité Universitätsmedizin Berlin, Germany;6. Klinik und Poliklinik für Neurologie, Charité Universitätsmedizin Berlin, Germany |
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Abstract: | Several reports have recently demonstrated a detrimental role of Toll-like receptors (TLR) in cerebral ischemia, while there is little information about the endogenous ligands which activate TLR-signaling. The myeloid related proteins-8 and-14 (Mrp8/S100A8; Mrp14/S100A9) have recently been characterized as endogenous TLR4-agonists, and thus may mediate TLR-activation in cerebral ischemia. Interestingly, not only TLR-mRNAs, but also Mrp8 and Mrp14 mRNA were found to be induced in mouse brain between 3 and 48 h after transient 1 h focal cerebral ischemia/reperfusion. Mrp-protein was expressed in the ischemic hemisphere, and co-labeled with CD11b-positive cells. To test the hypothesis that Mrp-signaling contributes to the postischemic brain damage, we subjected Mrp14-deficient mice, which also lack Mrp8 protein expression, to focal cerebral ischemia. Mrp14-deficient mice had significantly smaller lesion volumes when compared to wild-type littermates (130 ± 16 mm3 vs. 105 ± 28 mm3) at 2 days after transient focal cerebral ischemia (1 h), less brain swelling, and a reduced macrophage/microglia cell count in the ischemic hemisphere. We conclude that upregulation and signaling of Mrp-8 and-14 contribute to neuroinflammation and the progression of ischemic damage. |
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