Mrp-8 and -14 mediate CNS injury in focal cerebral ischemia.

Gina Ziegler, Vincent Prinz, Marcus W Albrecht, Denise Harhausen, Uldus Khojasteh, Wolfgang Nacken, Matthias Endres, Ulrich Dirnagl, Wilfried Nietfeld, George Trendelenburg

Max-Planck-Institute for Molecular Genetics, Ihnestr.73, 14195 Berlin, Germany.

Biochimica et biophysica acta 2009 Dec

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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 mm(3) vs. 105+/-28 mm(3)) 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.

Citation

Gina Ziegler, Vincent Prinz, Marcus W Albrecht, Denise Harhausen, Uldus Khojasteh, Wolfgang Nacken, Matthias Endres, Ulrich Dirnagl, Wilfried Nietfeld, George Trendelenburg. Mrp-8 and -14 mediate CNS injury in focal cerebral ischemia. Biochimica et biophysica acta. 2009 Dec;1792(12):1198-204