Vitamin D can mitigate sepsis-associated neurodegeneration by inhibiting exogenous histone-induced pyroptosis and ferroptosis: Implications for brain protection and cognitive preservation

作者：Yibing Sun, PU Zhi-lin, Hailin Zhao, Yuxuan Deng, Jing Zhang, Shiwei Li, Yingying Jiang, Ming Sun, Jinpiao Zhu, Azeem Alam, Daqing Ma, Ruquan Han · 发表于：Brain Behavior and Immunity · 年份：2024 · DOI：10.1016/j.bbi.2024.11.019 · 被引用次数：12 · 研究领域：Vitamin D Research Studies、Inflammasome and immune disorders、Ferroptosis and cancer prognosis

BACKGROUND: Sepsis-induced neurodegeneration and cognitive dysfunction remain critical challenges worldwide. Vitamin D was reported to reduce neuronal injury and neurotoxicity and its deficiency was associated with neurocognitive disorders. This study investigates the mechanisms by which vitamin D exerts neuroprotective potential against damage-associated molecular patterns (DAMPs), specifically extracellular histones, in sepsis-related brain dysfunction. METHODS: The cultured mouse hippocampal neuronal HT22 cells were exposed to 20 µg/ml exogenous histone for 24 h to induce pyroptosis and ferroptosis in the presence or absence of the active form of vitamin D, calcitriol (1 nM). A cecal ligation and puncture mouse sepsis model was used to evaluate histone release and pyroptosis/ferroptosis biomarkers in the brain together with neurobehavioral performance with or without calcitriol treatment (1 µg/kg, i.p. injection) at 24 h or 1 week after sepsis onset. RESULTS: In vitro, histone exposure triggered both pyroptosis and ferroptosis in neuronal cells, which was significantly suppressed by calcitriol treatment with the reduced expression of caspase-1 by 38 %, GSDMD by 30 %, ACSL4 by 33 %, and the increased expression of GPX4 by 35 % (n = 6, P < 0.05). Similarly, in vivo, calcitriol treatment inhibited both neuronal pyroptosis and ferroptosis by reducing expression of pyroptosis marker, GSDMD/NeuN (11.6 ± 1.2 % vs. 19.4 ± 1.1 %) and increasing expression of ferroptosis marker, GPX...