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 ischemiaactivated 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.

Preconditioning with rHMGB1 ameliorates lung ischemia–reperfusion injury through inhibiting alveolar macrophages pyroptosis via Keap1/Nrf2/HO-1 signal pathway

“…The current study demonstrated that rHMGB1 preconditioning provides protection against lung damage induced by lung I/R. Our nding is consistent with the previous results in organs IR injury [17][18][19]31]. Our research and others suggest that rHMGB1 preconditioning, as a prevention strategy, might have potential clinical signi cance.…”

“…HMGB1 (high-mobility group box 1), as a kind of damage signal molecule, can be recognized and has closely correlation to initiate the innate in ammatory response [15][16]. Studies suggest that preconditioning with recombinant HMGB1 (rHMGB1) can protect against myocardial, kidney, and cerebral I/R injury [17][18][19]. In addition, HMGB1 has the function of activating reactive oxygen species and induce oxidative stress [20][21].…”

Neutrophil-mediated and low density lipoprotein receptor-mediated dual-targeting nanoformulation enhances brain accumulation of scutellarin and exerts neuroprotective effects against ischemic stroke

“…It is generally evidenced that inammatory responses and cell apoptosis in neuronal injury aer ischemia/reperfusion are mediated by HMGB1, Toll-like receptors and NF-kB activation. 23,26 Recent researchs considered that TLR2/4 signaling could activate both the MyD88-dependent pathway and the TRAM/TRIF-dependent signaling pathway in macrophages. 27 TRAF6 is required for MyD88-dependent TLRs/NF-kB activation.…”

“…28,29 Given the fact that calcium overload usually results from alterations of intracellular signaling pathways, we further hypothesize that the dualtargeting STA-encapsulated nanoformulation can alter signaling pathways involved in inammatory responses, neutrophils inltration and calcium overload, for example, the well-established HMGB1/Toll-like receptors/NF-kB activation pathway. 23,26,51 With this in mind, we investigated whether treatment with Angiopep-2-PGP-STA-PEG-PAMAM NPs would alter the endogenous mRNAs and proteins expression of involved in the HMGB1/TLRs/MyD88/TRIF/NF-kB signaling pathway aer ischemic stroke. In this study, we evaluated the mRNA and protein expressions of major subgroups of HMGB1/TLRs/ MyD88/TRIF signaling pathways involved in inammation and cell apoptosis aer ischemic stroke.…”

“…Extracellular HMGB-1 activates its receptor TLR4, thereby promoting the activation of NF-kB. 26 The TRAM/ TRIF pathway is involved in the regulation of other genes in response to TLR2 and TLR4 ligands. 27 Tumor necrosis factor receptor associated factor 6 (TRAF6) and interleukin-1 receptor-associated kinase-4 (IRAK-4) have been shown to play essential roles in TLR-4-mediated signaling.…”