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

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.

Mots clés: S100A8; S100A9; Toll-like receptor; MCAO; knockout mice

Gina Ziegler, Vincent Prinz, Marcus W. Albrecht, Denise Harhausen, Uldus Khojasteh, et al.. Mrp-8 and-14 mediate CNS injury in focal cerebral ischemia. Biochimica et Biophysica Acta - Molecular Basis of Disease, 2009, 1792 (12), pp.1198. ⟨10.1016/j.bbadis.2009.10.003⟩. ⟨hal-00537259⟩