HMBG1 mediates ischemia-reperfusion injury by TRIF-adaptor independent Toll-like receptor 4 signaling

• Published in: Journal of cerebral blood flow and metabolism Vol. 31; no. 2; pp. 593 - 605
• Main Authors: Yang, Qing-Wu, Lu, Feng-Lin, Zhou, Yu, Wang, Lin, Zhong, Qi, Lin, Sen, Xiang, Jing, Li, Jing-Cheng, Fang, Chuan-Qing, Wang, Jing-Zhou
• Format: Journal Article
• Language: English
• Published: London, England SAGE Publications 01.02.2011; Nature Publishing Group; Sage Publications Ltd
• Subjects: Aged; Animals; Biological and medical sciences; Blotting, Western; Body Water - metabolism; Brain - pathology; Brain Chemistry; Cells, Cultured; Cerebral Infarction - pathology; Electrophoretic Mobility Shift Assay; Enzyme-Linked Immunosorbent Assay; Female; HMGB1 Protein - physiology; Humans; Macrophages - metabolism; Male; Medical sciences; Membrane Glycoproteins - genetics; Membrane Glycoproteins - physiology; Mice; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Mutant Chimeric Proteins - metabolism; Neurology; Neuropharmacology; Neuroprotective agent; Original; Pharmacology. Drug treatments; Receptors, Interleukin-1 - genetics; Receptors, Interleukin-1 - physiology; Reperfusion Injury - pathology; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction - genetics; Signal Transduction - physiology; Toll-Like Receptor 4 - genetics; Toll-Like Receptor 4 - physiology; Vascular diseases and vascular malformations of the nervous system; acute cerebral infarct; HMGB1; ischemia–reperfusion injury; TLR4; Vascular disease; ischemia-reperfusion injury; Cerebral infarction; Nervous system diseases; Ischemia reperfusion; Central nervous system disease; Cardiovascular disease; Cerebrovascular disease; Cerebral disorder
• ISSN: 0271-678X; 1559-7016
• DOI: 10.1038/jcbfm.2010.129

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.