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

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• 作者：Gina Ziegler ; Vincent Prinz ; Marcus W. Albrecht ; Denise Harhausen ; Uldus Khojasteh ; Wolfgang Nacken ; Matthias Endres ; Ulrich Dirnagl ; Wilfried Nietfeld ; George Trendelenburg
• 关键词：S100A8 ; S100A9 ; Toll-like receptor ; MCAO ; Knockout mice
• 刊名：Biochimica et Biophysica Acta (BBA)/Molecular Basis of Disease
• 出版年：2009
• 出版时间：December 2009
• 年：2009
• 卷：1792
• 期：12
• 页码：1198-1204
• 全文大小：611 K

文摘

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.