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骨化三醇通过VDR/Ca2+/细胞焦亡信号通路逆转脓毒症免疫抑制
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| 篇名： | 骨化三醇通过VDR/Ca2+/细胞焦亡信号通路逆转脓毒症免疫抑制 |
| TITLE： | Calcitriol reverses sepsis-induced immunosuppression via VDR/Ca2+/pyroptosis signaling pathway |
| 摘要： | 目的 探讨骨化三醇对脓毒症免疫抑制的影响及可能机制。方法采用盲肠结扎穿孔术（CLP）建立脓毒症免疫抑制小鼠模型，检测假手术组、CLP组和骨化三醇（1μg/kg）组小鼠7d生存率和血清中肿瘤坏死因子α（TNF-α）、白细胞介素6（IL-6）、IL-1β水平，观察肺组织形态学变化。选用小鼠巨噬细胞系RAW264.7细胞建立脂多糖（LPS）耐受细胞（即脓毒症免疫抑制细胞模型），检测培养基组、LPS组、LPS耐受组和骨化三醇（5μmol/L）组细胞上清液中TNF-α、IL-6水平和细胞中IL-1β、核苷酸结合结构域富含亮氨酸重复序列和含热蛋白结构域受体3（NLRP3）、IL-18、胱天蛋白酶1（caspase-1）mRNA表达量，以及碘化丙啶（PI）阳性率、caspase-1活性、乳酸脱氢酶（LDH）漏出率和Ca2+水平。结果与CLP组比较，骨化三醇组小鼠的7d生存率和血清中TNF-α、IL-6和IL-1β水平均显著升高（P＜0.05），肺组织损伤明显减轻。与LPS耐受组比较，骨化三醇组细胞上清液中TNF-α和IL-6水平，以及细胞中IL-1β、NLRP3、IL-18、caspase-1mRNA表达量和PI阳性率、caspase-1活性、LDH漏出率、Ca2+水平均显著升高（P＜0.05）。结论骨化三醇可逆转脓毒症免疫抑制，该作用机制可能是通过骨化三醇与维生素D受体结合，从而促进内质网释放Ca2+，进而驱动NLRP3/caspase-1介导的细胞焦亡途径来实现的。 |
| ABSTRACT： | OBJECTIVE To investigate the effects of calcitriol on sepsis-induced immunosuppression and its potential mechanism. METHODS A sepsis-induced immunosuppression mice model was established using cecal ligation and puncture （CLP）. The 7-day survival rate， serum levels of tumor necrosis factor- α （TNF- α）， interleukin-6 （IL-6）， and IL-1β were determined in sham operation group， CLP group and calcitriol group （1 μg/kg）； the morphological changes of lung tissue in mice were observed. Lipopolysaccharide （LPS） tolerance macrophage models （representing sepsis-induced immunosuppression） were established using mice macrophage cell line RAW264.7 cells. The levels of TNF-α and IL-6 in cell supernatants as well as mRNA expressions of IL-1β， nucleotide-binding domain leucine-rich repeat and pyrin domain-containing receptor 3 （NLRP3）， IL-18 and caspase-1 were assessed in culture medium group， LPS group， LPS tolerance group， and calcitriol （5 μmol/L） group. The following parameters were measured： propidium iodide （PI）-positive cell ratio， caspase-1 activity， lactate dehydrogenase （LDH） release， and Ca2+ levels. RESULTS Compared with CLP group， 7-day survival rate and serum levels of TNF-α， IL-6 and IL-1β were increased significantly in calcitriol group （P＜0.05）. Additionally， pulmonary tissue damage was markedly attenuated in calcitriol group. Compared with LPS tolerance group， the levels of TNF-α and IL-6 in cell supernatants， mRNA expressions of IL- 1β， NLRP3， IL-18 and caspase-1， PI-positive cell ratio， caspase-1 activity， LDH release， and Ca2+ levels were all increased significantly in calcitriol group （P＜0.05）. CONCLUSIONS Calcitriol can reverse sepsis-induced immunosuppression， and the mechanism of action may be E-mail：yarfwy@163.com achieved by the binding of calcitriol to vitamin D receptor，which promotes the release of Ca2+ from the endoplasmic reticulum， thereby driving the NLRP3/caspase-1-mediated pyroptosis pathway. |
| 期刊： | 2025年第36卷第18期 |
| 作者： | 尚圣兰；邹硕；魏宇琪；余梦辰；周帆；赵燕；余爱荣 |
| AUTHORS： | SHANG Shenglan，ZOU Shuo，WEI Yuqi，YU Mengchen，ZHOU Fan，ZHAO Yan，YU Airong |
| 关键字： | 骨化三醇；脓毒症；免疫抑制；细胞焦亡；Ca2+ |
| KEYWORDS： | calcitriol； sepsis； immunosuppression； pyroptosis； Ca2+ |
| 阅读数： | 5 次 |
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