Mrp-8 and-14 mediate CNS injury in focal cerebral ischemia
Résumé
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 48h after transient 1h focal cerebral ischemia/reperfusion. Mrp-protein was expressed in the ischemic hemisphere, and co-labelled 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 wildtype littermates (130 ± 16 mm vs. 105 ± 28 mm) at two days after transient focal cerebral ischemia (1h), 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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