Zhou Ting, Zhang Ziyao, Zhan Yawen, Wang Meiying, Wu Mi, Weng Xiufang, Xu Younian
Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Front Immunol. 2025 May 23;16:1583235. doi: 10.3389/fimmu.2025.1583235. eCollection 2025.
Sepsis associated acute respiratory distress syndrome (ARDS), is a life-threatening condition characterized by severe pulmonary inflammation. Previous research has suggested that allergic immune diseases are associated with a lower risk of sepsis. Therefore, we hypothesized that certain molecules involved in type 2 inflammation are beneficial for the outcome of sepsis associated ARDS. Thymic stromal lymphopoietin (TSLP) is known to promote Th2 responses in allergic disease, however, its role in sepsis associated ARDS remains limited.
To investigate the role of TSLP in sepsis associated lung injury, we administered exogenous recombinant TSLP to wild-type mice, followed by lipopolysaccharide (LPS) challenge. At 24 hours post-treatment, bronchoalveolar lavage fluid (BALF) and lung tissues were collected for analysis. The ratio, number, phenotype, and function of immune cells and cytokine levels were measured. Additionally, murine bone marrow-derived macrophages (BMDMs) were prepared and stimulated with LPS and TSLP to further verify our findings experimentally. To explore the molecular mechanisms of TSLP's effect, analysis of transcriptome sequencing and single-cell transcriptome sequencing and subsequent experiments were performed.
In LPS-induced acute lung injury models, pretreatment with TSLP significantly alleviated lung injury, suppressed inflammatory cytokines secretion, and reduced macrophages and neutrophils infiltration. In addition, TSLP treatment significantly inhibited M1 macrophage polarization and promoted M2 macrophage differentiation. Transcriptome sequencing suggested IFN-γ as a potential target of TSLP, and single-cell transcriptome sequencing showed that innate like T cells are important source of IFN-γ. Consistently, flow cytometry showed that proportion of IFN-γ-producing iNKT cells was decreased by TSLP administration in the acute lung injury model. Intriguingly, Jα18 mice, which are completely deficient in invariant natural killer T (iNKT) cells, exhibited not only significantly less severe lung inflammation but also a notably higher degree of anti-inflammatory Arg1 M2 macrophages infiltration when compared with their LPS-sensitized wild-type counterparts.
These findings not only underscore the crucial role of TSLP in the regulation of sepsis-associated ARDS but also demonstrate its potential clinical value as both a predictive biomarker for early detection and a molecular target for therapeutic intervention.
脓毒症相关急性呼吸窘迫综合征（ARDS）是一种以严重肺部炎症为特征的危及生命的病症。先前的研究表明，过敏性免疫疾病与脓毒症风险较低相关。因此，我们推测参与2型炎症的某些分子对脓毒症相关ARDS的预后有益。胸腺基质淋巴细胞生成素（TSLP）已知在过敏性疾病中促进Th2反应，然而，其在脓毒症相关ARDS中的作用仍然有限。
为了研究TSLP在脓毒症相关肺损伤中的作用，我们给野生型小鼠施用外源性重组TSLP，随后进行脂多糖（LPS）攻击。在治疗后24小时，收集支气管肺泡灌洗液（BALF）和肺组织进行分析。测量免疫细胞的比例、数量、表型和功能以及细胞因子水平。此外，制备小鼠骨髓来源的巨噬细胞（BMDM）并用LPS和TSLP刺激以通过实验进一步验证我们的发现。为了探索TSLP作用的分子机制，进行了转录组测序和单细胞转录组测序分析以及后续实验。
在LPS诱导的急性肺损伤模型中，TSLP预处理显著减轻了肺损伤，抑制了炎性细胞因子分泌，并减少了巨噬细胞和中性粒细胞浸润。此外，TSLP治疗显著抑制M1巨噬细胞极化并促进M2巨噬细胞分化。转录组测序表明IFN-γ是TSLP的潜在靶点，单细胞转录组测序显示固有样T细胞是IFN-γ的重要来源。一致地，流式细胞术显示在急性肺损伤模型中，TSLP给药降低了产生IFN-γ的不变自然杀伤T（iNKT）细胞的比例。有趣的是，与LPS致敏的野生型对照相比，完全缺乏不变自然杀伤T（iNKT）细胞的Jα18小鼠不仅肺部炎症明显减轻，而且抗炎性Arg1 M2巨噬细胞浸润程度明显更高。
这些发现不仅强调了TSLP在脓毒症相关ARDS调节中的关键作用，还证明了其作为早期检测的预测生物标志物和治疗干预分子靶点的潜在临床价值。
