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. Interpretation: 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. ANN NEUROL 2011;70:646-656
