HMBG1 mediates ischemia-reperfusion injury by TRIF-adaptor independent Toll-like receptor 4 signaling.
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-containing adaptor-inducing interferon-β knockout mice (TRIF(-/-)) and evaluated the activity and expression of TRIF pathway-related kinases. The results suggest that the TRIF pathway is not likely to be involved in TLR4-mediated ischemia brain injury. Finally, we found that TLR4 expressed by immigrant macrophages was involved in the development of ischemic brain damage. These results suggest that HMBG1 mediates ischemia-reperfusion injury by TRIF-adaptor independent Toll-like receptor 4 signaling. The TLR4 expressed by immigrant macrophages may be involved in the development of ischemic brain damage.
Yang
Qing-Wu
QW
Department of Neurology, Daping Hospital, The Third Military Medical University, Yuzhong District, Chongqing, China. yangqwmlys@hotmail.com
Lu
Feng-Lin
FL
Zhou
Yu
Y
Wang
Lin
L
Zhong
Qi
Q
Lin
Sen
S
Xiang
Jing
J
Li
Jing-Cheng
JC
Fang
Chuan-Qing
CQ
Wang
Jing-Zhou
JZ
D000368:Aged; D000818:Animals; D015153:Blotting, Western; D001834:Body Water / Q000378:metabolism; D001921:Brain / Q000473:pathology; D001923:Brain Chemistry; D002478:Cells, Cultured; D002544:Cerebral Infarction / Q000473:pathology; D024202:Electrophoretic Mobility Shift Assay; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D024243:HMGB1 Protein / Q000502:physiology*; D006801:Humans; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D050506:Mutant Chimeric Proteins / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000502:physiology*; D015427:Reperfusion Injury / Q000473:pathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000502:physiology*
D024243:HMGB1 Protein; D008562:Membrane Glycoproteins; D050506:Mutant Chimeric Proteins; D017472:Receptors, Interleukin-1; C499045:TIRAP protein, mouse; D051197:Toll-Like Receptor 4