Regulatory T lymphocytes are important targets for the treatment of acute respiratory distress syndrome (ARDS). IL-35 is a newly identified IL-12 cytokine family member that plays an important protective role in a variety of immune system diseases by regulating Treg cell differentiation; however, the role of IL-35 in the pathogenesis of ARDS is still unclear. Here, we found that IL-35 was significantly elevated in adult patients with ARDS compared to controls. Additionally, IL-35 was positively and significantly correlated with IL-6, IL-10 and the oxygenation index (PaO2/FiO2 ratio) but negatively correlated with TNF-α, IL-1β and APACHE II score during ARDS. Moreover, the proportion of Treg/CD4⁺ cells in the peripheral blood of ARDS patients and the expression of NF-κB in PMBCs were significantly higher than in healthy individuals. Recombinant IL-35 improved survival in a murine model of CLP-induced ARDS. Additionally, IL-35 administration decreased the inflammatory response, as reflected by lower levels of cytokines (including IL-2, TNF-α, IL-1β and IL-6) and less lung damage in CLP-induced ARDS. Furthermore, recombinant IL-35 reduced the apoptosis of lung tissue and the expression of NF-κB signalling in a CLP-induced ARDS model and increased the proportion of Treg cells in spleen and peripheral blood. In vitro experiments revealed that IL-35 can affect the phosphorylation of STAT5 during differentiation of naïve CD4⁺ T lymphocytes into Foxp3⁺Helios⁺ Tregs. Our findings suggest that IL-35 attenuates ARDS by promoting the differentiation of naïve CD4⁺ T cells into Foxp3⁺Helios⁺ Tregs, thereby providing a novel tool for anti-ARDS therapy.

调节性 T 淋巴细胞是治疗急性呼吸窘迫综合征 (ARDS) 的重要靶点。IL-35是新发现的IL-12细胞因子家族成员，通过调节Treg细胞分化，在多种免疫系统疾病中发挥重要保护作用；然而，IL-35在ARDS发病机制中的作用仍不清楚。在这里，我们发现与对照组相比，成年 ARDS 患者的 IL-35 显着升高。此外，IL-35 与 IL-6、IL-10 和氧合指数（PaO2/FiO2 比值）呈显着正相关，但与 ARDS 期间的 TNF-α、IL-1β 和 APACHE II 评分呈负相关。此外，Treg/CD4 ^+的比例ARDS患者外周血细胞和PMBCs中NF-κB的表达均显着高于健康人。重组 IL-35 改善了 CLP 诱导的 ARDS 小鼠模型的存活率。此外，IL-35 给药降低了炎症反应，这反映在较低水平的细胞因子（包括 IL-2、TNF-α、IL-1β 和 IL-6）和 CLP 诱导的 ARDS 中较少的肺损伤。此外，重组 IL-35 减少了 CLP 诱导的 ARDS 模型中肺组织的凋亡和 NF-κB 信号的表达，并增加了脾脏和外周血中 Treg 细胞的比例。体外实验表明，在幼稚 CD4 ⁺ T 淋巴细胞分化为 Foxp3 ⁺ Helios ^{+的过程中，IL-35 可以影响 STAT5 的磷酸化}Tregs。我们的研究结果表明，IL-35 通过促进幼稚 CD4 ⁺ T 细胞分化为 Foxp3 ⁺ Helios ⁺ Tregs 来减轻 ARDS，从而为抗 ARDS 治疗提供了一种新工具。