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

• Published in: Biochimica et biophysica acta 2009-12, Vol.1792 (12), p.1198-1204
• Main Authors: Ziegler, Gina, Prinz, Vincent, Albrecht, Marcus W., Harhausen, Denise, Khojasteh, Uldus, Nacken, Wolfgang, Endres, Matthias, Dirnagl, Ulrich, Nietfeld, Wilfried, Trendelenburg, George
• Format: Article
• Language: English
• Subjects: Animals; Brain Ischemia - metabolism; Brain Ischemia - pathology; Calgranulin A - physiology; Calgranulin B - physiology; Central Nervous System - injuries; Central Nervous System - metabolism; Gene Expression Profiling; Immunoenzyme Techniques; Inflammation - etiology; Inflammation - pathology; Knockout mice; MCAO; Mice; Mice, Inbred C57BL; Mice, Knockout; Neurons - pathology; Oligonucleotide Array Sequence Analysis; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; RNA, Messenger - metabolism; S100A8; S100A9; Toll-like receptor
• ISSN: 0925-4439; 0006-3002; 1879-260X
• DOI: 10.1016/j.bbadis.2009.10.003

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.