HMBG1 Mediates Ischemia—Reperfusion Injury by TRIF-Adaptor Independent Toll-Like Receptor 4 Signaling

Abstract

High-mobility group protein box-1 (HMGB1) has recently been recognized as a novel candidate in a specific upstream pathway promoting inflammation after brain ischemia. However, its downstream pathway and underlying mechanism have yet to be elucidated. The HMGB1 level in the acute cerebral infarct (ACI) group was significantly increased compared with that of control group, and correlated with the severity of neurologic impairment of ACI patients. Further, recombinant human HMGB1 (rhHMGB1) had no effect on microglia derived from mice lacking the Toll-like receptor 4 (TLR4−/–). Intracerebroventricular injection of rhHMGB1 in TLR4+/+ mice cause significantly more injury after cerebral ischemia–reperfusion than control group. But, TLR4−/– mice administered with rhHMGB1 showed moderate impairment after ischemia–reperfusion than TLR4+/+ mice. To determine the potential downstream signaling of HMGB1/TLR4 in cerebral ischemic injury, we used the ischemic–reperfusion model with Toll/interleukin-1 receptor domain-co...