Preconditioning with recombinant high‐mobility group box 1 induces ischemic tolerance in a rat model of focal cerebral ischemia–reperfusion

• Published in: Journal of neurochemistry Vol. 137; no. 4; pp. 576 - 588
• Main Authors: Wang, Chen, Liu, Xiao‐Xi, Huang, Kai‐Bin, Yin, Su‐Bing, Wei, Jing‐Jing, Hu, Ya‐Fang, Gu, Yong, Zheng, Guo‐Qing
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.05.2016
• Subjects: Animals; Brain damage; Brain Ischemia - metabolism; Brain Ischemia - pathology; Brain Ischemia - therapy; Cell Line; HMGB1; HMGB1 Protein - therapeutic use; IRAK‐M; Ischemia; Ischemic Preconditioning - methods; Ligands; Male; Mice; microglia; Neurochemistry; neuroprotection; Phosphorylation; preconditioning; Rats; Rats, Wistar; Recombinant Proteins - therapeutic use; Reperfusion Injury - metabolism; Reperfusion Injury - pathology; Reperfusion Injury - therapy; TLR4; IRAK-M; HMGB1; TLR4; microglia; neuroprotection; preconditioning
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.13611

Preconditioning with ligands of toll‐like receptors (TLRs) is a powerful neuroprotective approach whereby a low dose of stimulus confers significant protection against subsequent substantial brain damage by reprogramming the ischemia‐activated TLRs signaling. Herein, we aim to explore whether preconditioning with recombinant high‐mobility group box 1 (rHMGB1), one of the TLRs ligands, decreases cerebral ischemia–reperfusion injury (IRI). Rats were intracerebroventricularly pretreated with rHMGB1, 1 or 3 days before induction of middle cerebral artery occlusion. Results showed that preconditioning with rHMGB1 1 day, but not 3 days, prior to ischemia dramatically reduced neurological deficits, infarct size, brain swelling, cell apoptosis, and blood–brain barrier permeability. Interleukin‐1R‐associated kinase‐M (IRAK‐M), a critical negative regulator of TLRs signaling, was robustly increased in response to brain IRI and was further elevated by rHMGB1 pretreatment, indicating its role associated with the rHMGB1 preconditioning‐mediated ischemic tolerance. In vitro and in vivo assays indicated that the induced IRAK‐M expression was localized in microglia. In addition, TLR4 specific inhibitor TAK‐242 abolished the neuroprotective effects and the induction of IRAK‐M offered by rHMGB1 preconditioning. Collectively, our study demonstrates that rHMGB1 preconditioning is neuroprotective during cerebral IRI, which is associated with activated TLR4/IRAK‐M signaling in microglia. We found that high‐mobility group box 1 (HMGB1) pretreatment conditioned the brain against subsequent ischemia–reperfusion injury. We propose the following mechanism for HMGB1 preconditioning‐mediated ischemic tolerance: through toll‐like receptor TLR4, HMGB1 preconditioning magnifies the up‐regulation of interleukin‐1R‐associated kinase‐M (IRAK‐M) induced by ischemia‐reperfusion in microglia, resulting in the decreased phosphorylation of IRAK‐1. These findings are helpful in understanding the endogenous mechanisms that counteract ischemic insults. We found that high‐mobility group box 1 (HMGB1) pretreatment conditioned the brain against subsequent ischemia–reperfusion injury. We propose the following mechanism for HMGB1 preconditioning‐mediated ischemic tolerance: through toll‐like receptor TLR4, HMGB1 preconditioning magnifies the up‐regulation of interleukin‐1R‐associated kinase‐M (IRAK‐M) induced by ischemia‐reperfusion in microglia, resulting in the decreased phosphorylation of IRAK‐1. These findings are helpful in understanding the endogenous mechanisms that counteract ischemic insults.