Mrp-8 and -14 mediate CNS injury in focal cerebral ischemia.
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.
Ziegler
Gina
G
Max-Planck-Institute for Molecular Genetics, Ihnestr.73, 14195 Berlin, Germany.
Prinz
Vincent
V
Albrecht
Marcus W
MW
Harhausen
Denise
D
Khojasteh
Uldus
U
Nacken
Wolfgang
W
Endres
Matthias
M
Dirnagl
Ulrich
U
Nietfeld
Wilfried
W
Trendelenburg
George
G
D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology; D040501:Calgranulin A / Q000502:physiology*; D040502:Calgranulin B / Q000502:physiology*; D002490:Central Nervous System / Q000293:injuries* / Q000378:metabolism; D020869:Gene Expression Profiling; D007124:Immunoenzyme Techniques; D007249:Inflammation / Q000209:etiology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D040501:Calgranulin A; D040502:Calgranulin B; D012333:RNA, Messenger