Sun Mengfei, Yang Qianqian, Tan Yingshuai, Hu Chunling, Zhao Shilong, Lu Xiaoxiao, Gao Jing, Xing Lihua
Department of Respiratory Intensive Care Unit, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, China.
Inflammation. 2026 Jan 24;49(1):65. doi: 10.1007/s10753-026-02451-4.
ALI and ARDS are among the most common diseases in intensive care units, and are characterized by rapid onset and high mortality rates. Dysregulation of macrophage homeostasis is closely associated with the inflammatory cascade in ALI/ARDS. Transcription factors play critical roles in maintaining macrophage immune function. However, the mechanisms by which transcription factors and macrophages regulate the inflammatory imbalance in ALI/ARDS remain largely undefined. Here, we illustrate the role of DDIT3 in regulating macrophage immune function. Our comprehensive bioinformatics analysis revealed that DDIT3 is a key transcriptional regulator of ARDS with superior diagnostic potential. DDIT3 is highly expressed in macrophages and promotes M1 macrophage activation in ARDS patients, and in vivo/vitro models of ALI. DDIT3 deficiency significantly reduces the proportion of M1 macrophages and notably decreases in the secretion of inflammatory cytokines. RNA-seq and CUT&Tag analyses identified KLF10 as a target gene of DDIT3. Moreover, we demonstrated that the inhibition of KLF10 activity reversed the anti-inflammatory effect of DDIT3 silencing by restoring M1 macrophage polarization and inflammatory cytokine secretion. Our findings confirm that DDIT3 is a key regulator of macrophage polarization and inflammatory mediator secretion, suggesting that DDIT3 is a potential therapeutic target for ALI/ARDS.
The online version contains supplementary material available at 10.1007/s10753-026-02451-4.
急性肺损伤（ALI）和急性呼吸窘迫综合征（ARDS）是重症监护病房中最常见的疾病，其特点是起病迅速且死亡率高。巨噬细胞内稳态失调与ALI/ARDS中的炎症级联反应密切相关。转录因子在维持巨噬细胞免疫功能中起关键作用。然而，转录因子和巨噬细胞调节ALI/ARDS中炎症失衡的机制在很大程度上仍不明确。在此，我们阐述了DNA损伤诱导转录因子3（DDIT3）在调节巨噬细胞免疫功能中的作用。我们全面的生物信息学分析表明，DDIT3是ARDS的关键转录调节因子，具有卓越的诊断潜力。DDIT3在巨噬细胞中高表达，并促进ARDS患者以及ALI体内/体外模型中M1巨噬细胞的活化。DDIT3缺陷显著降低M1巨噬细胞的比例，并显著减少炎症细胞因子的分泌。RNA测序（RNA-seq）和切割与标记分析（CUT&Tag）确定 Kruppel样因子10（KLF10）为DDIT3的靶基因。此外，我们证明抑制KLF10活性可通过恢复M1巨噬细胞极化和炎症细胞因子分泌来逆转DDIT3沉默的抗炎作用。我们的研究结果证实，DDIT3是巨噬细胞极化和炎症介质分泌的关键调节因子，表明DDIT3是ALI/ARDS的潜在治疗靶点。
在线版本包含可在10.1007/s10753-026-02451-4获取的补充材料。
