Toll-like receptor 4 contributes to poor outcome after intracerebral hemorrhage.
OBJECTIVE
Intracerebral hemorrhage (ICH) is a devastating stroke subtype in which perihematomal inflammation contributes to neuronal injury and functional disability. Histologically, the region becomes infiltrated with neutrophils and activated microglia followed by neuronal loss, but little is known about the immune signals that coordinate these events. This study aimed to determine the role of Toll-like receptor 4 (TLR4) in the innate immune response after ICH and its impact on neurobehavioral outcome.


METHODS
Transgenic mice incapable of TLR4 signaling and wild-type controls were subjected to striatal blood injection to model ICH. The perihematomal inflammatory response was then quantified by immunohistochemistry, whole brain flow cytometry, and polymerase chain reaction. The critical location of TLR4 signaling was determined by blood transfer experiments between genotypes. Functional outcomes were quantified in all cohorts using the cylinder and open field tests.


RESULTS
TLR4-deficient mice had markedly decreased perihematomal inflammation, associated with reduced recruitment of neutrophils and monocytes, fewer microglia, and improved functional outcome by day 3 after ICH. Moreover, blood transfer experiments revealed that TLR4 on leukocytes or platelets within the hemorrhage contributes to perihematomal leukocyte infiltration and the neurological deficit.


CONCLUSIONS
Together, these data identify a critical role for TLR4 signaling in perihematomal inflammation and injury and indicate this pathway may be a target for therapeutic intervention.
Department of Neurology, School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. sansing@uchc.edu
Lauren H
LH
Sansing
Tajie H
TH
Harris
Frank A
FA
Welsh
Scott E
SE
Kasner
Christopher A
CA
Hunter
Katalin
K
Kariko
D000818:Animals; D001930:Brain Injuries / Q000235:genetics / Q000276:immunology*; D002543:Cerebral Hemorrhage / Q000235:genetics / Q000276:immunology*; D007249:Inflammation; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000172:deficiency* / Q000235:genetics / Q000276:immunology*
D051197:Toll-Like Receptor 4