High mobility group box 1 (HMGB1), when released extracellularly, plays a pivotal role in the development of spinal cord synapses and exacerbates autoimmune diseases within the central nervous system. In experimental autoimmune encephalomyelitis (EAE), a condition that models multiple sclerosis, the levels of extracellular HMGB1 and interleukin-33 (IL-33) have been found to be inversely correlated. However, the mechanism by which IL-33 deficiency enhances HMGB1 release during EAE remains elusive. Our study elucidates a potential signaling pathway whereby the absence of IL-33 leads to increased binding of P300/CBP-associated factor with HMGB1 in the nuclei of astrocytes, upregulating HMGB1 acetylation and promoting its release from astrocyte nuclei in the spinal cord of EAE mice. Conversely, the addition of IL-33 counteracts the TNF-α-induced increase in HMGB1 and acetylated HMGB1 levels in primary astrocytes. These findings underscore the potential of IL-33-associated signaling pathways as a therapeutic target for EAE treatment.
Animals ; Encephalomyelitis, Autoimmune, Experimental/metabolism* ; Astrocytes/metabolism* ; Interleukin-33/metabolism* ; HMGB1 Protein/metabolism* ; Acetylation ; Mice, Knockout ; Mice, Inbred C57BL ; p300-CBP Transcription Factors/metabolism* ; Mice ; Spinal Cord/metabolism* ; Cells, Cultured ; Female ; Signal Transduction

Objective This study aimed to explore the effects and mechanisms of chronic intermittent exposure to alcohol on fear,anxiety and depression behavior in post-traumatic stress disorder mice.Methods Thirty-six 8-week-old male C57BL/6J mice were randomly divided into a control group(Control),a traumatic stress disorder(PTSD)group and a chronic intermittent alcohol exposure(PTSD+Alcohol)group.The PTSD mice were prepared via the plantar electric shock method and then chroni-cally exposed to alcohol for 14 days.The fear,anxiety and depression behaviors of each group of mice were observed via a behav-ioral test.Western blotting was used to detect the expression levels of the microglial markers ionized calcium binding adapter molecule 1(IBA1),postsynaptic density protein 95(PSD95),and synaptotagmin Ⅰ(SYT1)in the hippocampal tissue of the mice in each group.Immunofluorescence staining was performed to assess the expression levels of IBA1 and Synaptophysin(SYN)in the hippocampal tissue.An enzyme-linked immunosorbent assay(ELISA)was used to measure the release of tumor necrosis fac-tor-α(TNF-α),interleukin-6(IL-6),and interleukin-1β(IL-1β)in the hippocampal tissue.Results Compared with those in the control group,the ratio of freezing time in the conditioned fear chamber significantly increased,the number of open arm entries decreased,the immobility time in the forced swim test increased in the PTSD group,and the expression of IBA1 protein and TNF-α release increased,with decreased expression of SYN,PSD95 and SYT1(all P＜0.05).Compared with the PTSD group,the PTSD+Alcohol group presented significantly increased freezing time in the conditioned fear chamber,decreased locomotor distance and time spent in the center zone in the open field test,increased IBA1 protein expression,and increased release of TNF-α and IL-1β(all P＜0.05).Conclusion Chronic intermittent alcohol exposure can aggravate fear,anxiety and depression in post-traumatic stress model mice,and the mechanism may be related to the activation of microglia.