[Frontiers in Bioscience S2, 1081-1091, June 1, 2010]
Targeting HMGB1/TLR4 signaling as a novel approach to treatment of cerebral ischemia
Qing-Wu Yang, Jing Xiang, Yu Zhou, Qi Zhong, Jing-Cheng Li
Department of Neurology, Daping Hospital, The Third Military Medical University, 10 Changjiang Branch Road, Yuzhong District, Chongqing 400042, China
Figure 1. HMGB1/TLR4 signaling pathways. HMGB1 binds TLR4 and signals through adaptor molecules via the Toll/IL-1 receptor-domain. TLR4 can then signal via MyD88, IRAK, and TRAF to NF-κB, as well as via Rac1, PI3K, and CDC42, and possibly via Akt and MAPKs. The signaling cascades that lead to release of NF-κB from the inhibitory IKK complex, consisting of IKKa , IKKb, and IKKg , are the main activators of NF-κB. After activation, NF-κB translocates into the nucleus and induces the transcription of proinflammatory immune mediators, such as TNF-α and IL-1b. TLR signaling is also mediated through another adaptor, TIR domain-containing adaptor protein (TRIF), which activates TANK-binding kinase1 (TBK1) and IKKξ, leads to the activation of IFN regulatory factor 3 (IRF3), and thereby activates interferon-b (IFN-b) and IFN-b-inducible genes.
Figure 2. Schematic representation of therapeutic strategies of HMGB1/TLR4 signaling for cerebral ischemia. Ischemic insult induces HMGB1 synthesis and acetylation in nucleus of neuronal cells and then HMGB1 is released into the extracellular space, thereby allowing its interactions with RAGE and TLR2/4 or other unknown receptors in neuronal cells and in microglia. The common signaling pathway involves activation of NF-κB to induce expression of HMGB1 and inflammatory mediators, which ultimately results in neuronal injury in cerebral ischemia. HMGB1 and TLR4 may be therapeutic targets for the treatment of cerebral ischemia. Therapeutic strategies include anti-HMGB1 antibodies, HMGB1 A box protein, and LPS preconditioning. LPS preconditioned microglial cells do not recruit MyD88 to TLR4 and fail to activate IRAK-1 and NF-kB, and importantly, do not express NF-kB-dependent inflammatory genes (87). However, how HMGB1 preconditioning protects from ischemic injury remains unkown. ,"actively secreted" acetylated HMGB1; , "passively released" HMGB1.