Calcitriol reverses sepsis-induced immunosuppression via VDR/Ca<sup>2+</sup>/pyroptosis signaling pathway

SHANG Shenglan; ZOU Shuo; WEI Yuqi; YU Mengchen; ZHOU Fan; ZHAO Yan; YU Airong

doi:10.6039/j.issn.1001-0408.2025.18.03

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Calcitriol reverses sepsis-induced immunosuppression via VDR/Ca²⁺/pyroptosis signaling pathway

更新时间：2025-09-25

- Calcitriol reverses sepsis-induced immunosuppression via VDR/Ca²⁺/pyroptosis signaling pathway
- ZHONGGUO YAOFANG Vol. 36, Issue 18, Pages: 2232-2237(2025)
- 作者机构：
  
  1.武汉科技大学医学院，武汉　430065
  2.中部战区总医院临床药学科，武汉　430070
  3.湖北科技学院药学院，湖北咸宁　437100
- 作者简介：
- 基金信息：
- DOI：10.6039/j.issn.1001-0408.2025.18.03
  CLC： R965
- Received：13 May 2025，
  
  Revised：2025-08-12，
  
  Accepted：25 August 2025，
  
  Published：30 September 2025
- 稿件说明：
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尚圣兰,邹硕,魏宇琪,等.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[J].中国药房,2025,36(18):2232-2237.

SHANG Shenglan,ZOU Shuo,WEI Yuqi,et al.Calcitriol reverses sepsis-induced immunosuppression via VDR/Ca²⁺/pyroptosis signaling pathway[J].ZHONGGUO YAOFANG,2025,36(18):2232-2237.
尚圣兰,邹硕,魏宇琪,等.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[J].中国药房,2025,36(18):2232-2237. DOI： 10.6039/j.issn.1001-0408.2025.18.03.

SHANG Shenglan,ZOU Shuo,WEI Yuqi,et al.Calcitriol reverses sepsis-induced immunosuppression via VDR/Ca²⁺/pyroptosis signaling pathway[J].ZHONGGUO YAOFANG,2025,36(18):2232-2237. DOI： 10.6039/j.issn.1001-0408.2025.18.03.

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（1 μg/kg）组小鼠7 d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（5 μmol/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Ca

水平。

结果

与CLP组比较，骨化三醇组小鼠的7 d生存率和血清中TNF-α、IL-6和IL-1β水平均显著升高（

＜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-1 mRNA表达量和PI阳性率、caspase-1活性、LDH漏出率、Ca

水平均显著升高（

＜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Ca

，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 mi

ce 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 Ca

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 （

＜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 Ca

levels were all increased significantly in calcitriol group （

＜0.05）.

CONCLUSIONS

Calcitriol can reverse sepsis-induced immunosuppression， and the mechanism of action may be achieved by the binding of calcitriol to vitamin D receptor， which promotes the release of Ca

from the endoplasmic reticulum， thereby driving the NLRP3/caspase-1-mediated pyroptosis pathway.

关键词

Keywords

references

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HOTCHKISS R S ， MONNERET G ， PAYEN D . Sepsis-induced immunosuppression：from cellular dysfunctions to immunotherapy [J ] . Nat Rev Immunol ， 2013 ， 13 （ 12 ）： 862 - 874 .

CUTULI S L ， FERRANDO E S ， CAMMAROTA F ， et al . Update on vitamin D role in severe infections and sepsis [J ] . J Anesth Analg Crit Care ， 2024 ， 4 （ 1 ）： 4 .

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DENG D M ， LI X L ， LIU C ， et al . Systematic investigation on the turning point of over-inflammation to immunosuppression in CLP mice model and their characteristics [J ] . Int Immunopharmacol ， 2017 ， 42 ： 49 - 58 .

LEAF D E ， RAED A ， DONNINO M W ， et al . Rando-mized controlled trial of calcitriol in severe sepsis [J ] . Am J Respir Crit Care Med ， 2014 ， 190 （ 5 ）： 533 - 541 .

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Calcitriol reverses sepsis-induced immunosuppression via VDR/Ca2+/pyroptosis signaling pathway

DOI：10.6039/j.issn.1001-0408.2025.18.03

摘要

Abstract

关键词

Keywords

references

Calcitriol reverses sepsis-induced immunosuppression via VDR/Ca²⁺/pyroptosis signaling pathway