title: Ds-HMGB1 and fr-HMGB induce depressive behavior through neuroinflammation in contrast to nonoxid-HMGB1.
abstract: High mobility group box 1 (HMGB1) has been implicated as a key factor in several neuroinflammatory conditions. Our previous study suggested that the release of central HMGB1 acts as a late-phase mediator in lipopolysaccharide (LPS)-induced depression. Recent findings indicate that the redox state of HMGB1 is a critical determinant of its immunomodulatory properties. Here, we aimed to investigate the potential mechanisms that link the redox states of HMGB1 to depression in mice. Distinct redox forms of recombinant HMGB1 (rHMGB1) were used that included fully reduced HMGB (fr-HMGB1), which acted as a chemokine, and disulfide-HMGB1 (ds-HMGB1), which possessed cytokine activity. Fr-HMGB1 in vivo was partially oxidized into ds-HMGB1; thus, the mutant protein non-oxidizable chemokine-HMGB (nonoxid-HMGB1) was applied. Concurrent with depressive behavior induced by four-week stress exposure, the HMGB1 concentrations in the serum and cerebral cortex substantially increased. Therefore, a single dose of rHMGB1 (200ng/5μl/mice) or vehicle was administered to mice via intracerebroventricular (i.c.v.) injection. The receptor inhibitors of TLR4/RAGE/CXCR4 (TAK-242/FPS-ZM1/AMD3100) (3mg/kg) were intraperitoneally injected 30min prior to rHMGB1 treatment. Depressive-like behavior was measured 20h post i.c.v. injection. Administration of fr-HMGB1 prolonged the immobility duration in the tail suspension test (TST) and decreased sucrose preference. In addition to depressive behavior, the hippocampal TNF-α protein slightly increased. These depressive behaviors and upregulation of hippocampal TNF-α were alleviated or abrogated by pretreatment with the inhibitors AMD3100, FPS-ZM1, and TAK-242. Alternatively, nonoxid-HMGB1 failed to induce TNF-α protein or prolong the immobility duration. As expected, ds-HMGB1 administration substantially upregulated hippocampal TNF-α protein, increased the immobility time in the TST and decreased sucrose preference. Moreover, both glycyrrhizin and TAK-242 improved ds-HMGB1-induced depressive behavior. Furthermore, TAK-242 significantly blocked the upregulation of hippocampal TNF-α protein and protected hippocampal myelin basic protein from ds-HMGB1-induced reduction. These drugs had no effect on the total or central distance in the open field test. Collectively, this initial experiment demonstrates the role and receptor mechanisms of HMGB1 under different redox states on the induction of depressive-like behavior. Both ds-HMGB1 and fr-HMGB1 may induce depressive-like behavior in vivo mainly via neuroinflammatory response activation.
authors.affiliation: Lab of Stress Medicine, Department of Psychology and Mental Health, Second Military Medical University, Shanghai 200433, PR China.
authors.forename: Yong-Jie
authors.initials: YJ
authors.lastname: Lian
authors.affiliation: Lab of Stress Medicine, Department of Psychology and Mental Health, Second Military Medical University, Shanghai 200433, PR China.
authors.forename: Hong
authors.initials: H
authors.lastname: Gong
authors.affiliation: Team of Aviation Physical Examination, Air Force General Hospital of PLA, Beijing 100142, PR China.
authors.forename: Teng-Yun
authors.initials: TY
authors.lastname: Wu
authors.affiliation: Lab of Stress Medicine, Department of Psychology and Mental Health, Second Military Medical University, Shanghai 200433, PR China.
authors.forename: Wen-Jun
authors.initials: WJ
authors.lastname: Su
authors.affiliation: Lab of Stress Medicine, Department of Psychology and Mental Health, Second Military Medical University, Shanghai 200433, PR China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Lab of Stress Medicine, Department of Psychology and Mental Health, Second Military Medical University, Shanghai 200433, PR China.
authors.forename: Yuan-Yuan
authors.initials: YY
authors.lastname: Yang
authors.affiliation: Lab of Stress Medicine, Department of Psychology and Mental Health, Second Military Medical University, Shanghai 200433, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Peng
authors.affiliation: Department of Navy Medicine, Second Military Medical University, Shanghai 200433, PR China.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Lab of Stress Medicine, Department of Psychology and Mental Health, Second Military Medical University, Shanghai 200433, PR China.
authors.forename: Jiang-Rui
authors.initials: JR
authors.lastname: Zhou
authors.affiliation: Lab of Stress Medicine, Department of Psychology and Mental Health, Second Military Medical University, Shanghai 200433, PR China.
authors.forename: Chun-Lei
authors.initials: CL
authors.lastname: Jiang
authors.affiliation: Lab of Stress Medicine, Department of Psychology and Mental Health, Second Military Medical University, Shanghai 200433, PR China. Electronic address: cloudywang66@163.com.
authors.forename: Yun-Xia
authors.initials: YX
authors.lastname: Wang
mesh_terms: D059445:Anhedonia; D000818:Animals; D003863:Depression / Q000139:chemically induced* / Q000523:psychology*; D024243:HMGB1 Protein / Q000737:chemistry / Q000235:genetics* / Q000494:pharmacology*; D019417:Hindlimb Suspension; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000139:chemically induced* / Q000523:psychology*; D007274:Injections, Intraperitoneal; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009043:Motor Activity; D010084:Oxidation-Reduction; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology; D013315:Stress, Psychological / Q000523:psychology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D024243:HMGB1 Protein; C585491:HMGB1 protein, human; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha
keywords: Depression; HMGB1 protein; Myelin basic protein; Redox forms; TNF-α