title: From the Cover: Tetrachlorobenzoquinone Exerts Neurological Proinflammatory Activity by Promoting HMGB1 Release, Which Induces TLR4 Clustering within the Lipid Raft.
abstract: Tetrachlorobenzoquinone (TCBQ) is a confirmed active metabolite of a well-known environmental pollutant pentachlorophenol (PCP). Unfortunately, there is insufficient knowledge present available on TCBQ's toxicity. Our previous studies indicated that TCBQ induces inflammatory response in vivo and in vitro; however, its exact mechanism needs further investigation. Toll-like receptors (TLRs) play a crucial role in conveying of inflammatory signaling, whilst high-mobility group box 1 (HMGB1) functions as a transcription-enhancing nuclear protein that regulates inflammation. Indeed, this study demonstrated that TCBQ induces the secretion/translocation of HMGB1, which in turn activates its receptors, TLR family gene (especially TLR4) and receptor for advanced glycation end-products (RAGE) expressions. Consistently, the binding affinity of HMGB1 with its receptors also increased. In the case of HMGB1 or TLR4 deficiency, there were decreases in TCBQ-induced neuroinflammatory cytokine production and neuropathological changes, eg, neuronal loss, astrocyte and macrophage cells activation. Moreover, we found the mobilization of TLR4 into lipid rafts occurs in response to TCBQ exposure, lipid rafts disruptors weakened this effect, suggested lipid rafts play an essential role for TLR4-mediated signal transduction and target inflammatory cytokines expressions. In summary, our current findings revealed a previously unknown mechanism of TCBQ-induced neurological inflammation related to HMGB1-TLR4 signaling.
authors.forename: Juanli
authors.initials: J
authors.lastname: Fu
authors.forename: Qiong
authors.initials: Q
authors.lastname: Shi
authors.forename: Xiufang
authors.initials: X
authors.lastname: Song
authors.forename: Zixuan
authors.initials: Z
authors.lastname: Liu
authors.forename: Yawen
authors.initials: Y
authors.lastname: Wang
authors.forename: Yuxin
authors.initials: Y
authors.lastname: Wang
authors.forename: Erqun
authors.initials: E
authors.lastname: Song
authors.affiliation: Key Laboratory of Luminescence and Real-Time Analytical Chemistry (Southwest University), Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, People's Republic of China songyangwenrong@hotmail.com ysong@swu.edu.cn.
authors.forename: Yang
authors.initials: Y
authors.lastname: Song
mesh_terms: D000107:Acetylation; D000818:Animals; D016227:Benzoquinones / Q000633:toxicity*; D002467:Cell Nucleus / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D003593:Cytoplasm / Q000378:metabolism; D024243:HMGB1 Protein / Q000378:metabolism*; D006843:Hydrocarbons, Chlorinated / Q000633:toxicity*; D007249:Inflammation / Q000139:chemically induced*; D008297:Male; D021962:Membrane Microdomains / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009420:Nervous System / Q000378:metabolism / Q000473:pathology*; D016716:PC12 Cells; D010766:Phosphorylation; D021381:Protein Transport; D051381:Rats; D000067759:Receptor for Advanced Glycation End Products / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: D016227:Benzoquinones; D016207:Cytokines; D024243:HMGB1 Protein; D006843:Hydrocarbons, Chlorinated; D000067759:Receptor for Advanced Glycation End Products; D051197:Toll-Like Receptor 4; C000591600:tetrachlorobenzoquinone
keywords: HMGB1; ROS.; TLR; inflammation; lipid rafts; tetrachlorobenzoquinone