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Published on: July 25, 2011
Mrp-8 and -14 mediate CNS injury in focal cerebral ischemia
Gina Ziegler1, Vincent Prinz, Marcus W Albrecht
1Max-Planck-Institute for Molecular Genetics, Ihnestr.73, 14195 Berlin, Germany.
Abstract:
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.
Insights
Myeloid-related proteins (Mrp8/S100A8 and Mrp14/S100A9) activate Toll-like receptors (TLR) and worsen brain damage after stroke. Mice lacking these proteins showed reduced injury, suggesting Mrp8/14 signaling contributes to neuroinflammation and stroke progression.
Area of Science:
- Neuroscience
- Immunology
- Pathology
Background:
- Toll-like receptors (TLR) play a detrimental role in cerebral ischemia.
- Endogenous ligands that activate TLR signaling in this context are not well understood.
- Myeloid-related proteins-8 (Mrp8/S100A8) and -14 (Mrp14/S100A9) are identified as endogenous TLR4 agonists.
Purpose of the Study:
- To investigate the role of Mrp8 and Mrp14 in the progression of ischemic brain damage.
- To test the hypothesis that Mrp signaling contributes to post-ischemic brain injury.
Main Methods:
- Induction of focal cerebral ischemia/reperfusion in mouse models.
- Analysis of Toll-like receptor (TLR), Mrp8, and Mrp14 mRNA and protein expression in the ischemic brain.
- Comparison of lesion volume, brain swelling, and immune cell infiltration in Mrp14-deficient mice versus wild-type littermates.
Main Results:
- Mrp8 and Mrp14 mRNA were upregulated in the mouse brain post-ischemia.
- Mrp protein expression was observed in the ischemic hemisphere, co-localizing with CD11b-positive cells.
- Mrp14-deficient mice exhibited significantly smaller lesion volumes, reduced brain swelling, and decreased macrophage/microglia counts compared to wild-type controls.
Conclusions:
- Upregulation and signaling of Mrp8 and Mrp14 contribute to neuroinflammation.
- Mrp8/14 signaling exacerbates ischemic brain damage.
- Targeting Mrp8/14 may offer a therapeutic strategy for stroke.
