TLR-4 deficiency protects against focal cerebral ischemia and axotomy-induced neurodegeneration.
The pattern recognition receptor toll-like receptor (TLR)-4 mediates innate danger signaling in the brain, being activated in response to lipopolysaccharide. Until now, its role in the degenerating brain remained unknown. We here examined effects of a loss-of-function mutation of TLR-4 in mice submitted to transient focal cerebral ischemia and retinal ganglion cell (RGC) axotomy, which are highly reproducible and clinically relevant in vivo models of acute and subacute neuronal degeneration. We show that TLR-4 deficiency protects mice against ischemia and axotomy-induced RGC degeneration. Decreased phosphorylation levels of the mitogen-activated kinases ERK-1/-2, JNK-1/-2 and p38 together with reduced inducible NO synthase levels in injured neurons of TLR-4 mutant mice suggests that TLR-4 deficiency downscales parenchymal stress responses, thereby enhancing neuronal survival. At the same time, densities of MPO+ neutrophils and Iba1+ microglial cells were increased in the brains of TLR-4 mutant animals, pointing towards a futile inflammatory response aiming to compensate lost functions. Our data indicate that innate immunity may represent an attractive target for neuroprotective treatments in stroke and neurodegeneration.
Kilic
Ulkan
U
Department of Neurology, University Hospital Zürich, Frauenklinikstr. 26, CH-8091 Zürich, Switzerland.
Kilic
Ertugrul
E
Matter
Christian M
CM
Bassetti
Claudio L
CL
Hermann
Dirk M
DM
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D019771:Axotomy; D015153:Blotting, Western; D002545:Brain Ischemia / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D020287:In Situ Nick-End Labeling; D017078:Laser-Doppler Flowmetry; D008297:Male; D051379:Mice; D017628:Microglia / Q000276:immunology / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism; D048056:Mitogen-Activated Protein Kinase 9 / Q000378:metabolism; D009154:Mutation; D009410:Nerve Degeneration / Q000378:metabolism* / Q000473:pathology; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010766:Phosphorylation; D012165:Retinal Ganglion Cells / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000172:deficiency* / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D052247:Nitric Oxide Synthase Type II; D048056:Mitogen-Activated Protein Kinase 9; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048055:Mitogen-Activated Protein Kinase 8; D048051:p38 Mitogen-Activated Protein Kinases