title: Preconditioning with recombinant high-mobility group box 1 induces ischemic tolerance in a rat model of focal cerebral ischemia-reperfusion.
abstract: 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.
authors.affiliation: Department of Neurology, The Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.|Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
authors.forename: Xiao-Xi
authors.initials: XX
authors.lastname: Liu
authors.affiliation: Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
authors.forename: Kai-Bin
authors.initials: KB
authors.lastname: Huang
authors.affiliation: Department of Neurology, The Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.
authors.forename: Su-Bing
authors.initials: SB
authors.lastname: Yin
authors.affiliation: Department of Neurology, The Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.
authors.forename: Jing-Jing
authors.initials: JJ
authors.lastname: Wei
authors.affiliation: Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
authors.forename: Ya-Fang
authors.initials: YF
authors.lastname: Hu
authors.affiliation: Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Gu
authors.affiliation: Department of Neurology, The Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.
authors.forename: Guo-Qing
authors.initials: GQ
authors.lastname: Zheng
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D002460:Cell Line; D024243:HMGB1 Protein / Q000627:therapeutic use*; D019194:Ischemic Preconditioning / Q000379:methods*; D008297:Male; D051379:Mice; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000627:therapeutic use; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000628:therapy*
chemical_list: D024243:HMGB1 Protein; C104200:Hbp1 protein, rat; D011994:Recombinant Proteins
keywords: HMGB1; IRAK-M; TLR4; microglia; neuroprotection; preconditioning