Chuang Hsiao-Chi, Chang Jer-Hwa, Fan Yen-Yi, Hsieh Chia-Ling, Lee Yueh-Lun
School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Taiwan; Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan.
School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Taiwan; Division of Pulmonary Medicine, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Pulmonary Research Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
Biomed Pharmacother. 2024 Dec;181:117738. doi: 10.1016/j.biopha.2024.117738. Epub 2024 Dec 11.
Allergic asthma is a chronic disease tied to unusual immune reactions involving type 2 T helper (Th2) cells specific to allergens. Dendritic cells (DCs) play a crucial role in guiding T-cell responses. Regulatory T (Treg) cells have the ability to suppress effector T-cell responses, and interleukin (IL)-38 is involved in Treg cell differentiation. In this study, we explored impacts of IL-38 on the activation and function of DCs, and we then developed an IL-38-overexpressing adenovirus (Ad-IL38) to evaluate its effectiveness in treating allergic asthma in mice through the adaptive transfer of Ad-IL38-infected DCs (IL38-DCs). Treating lipopolysaccharide (LPS)-activated bone marrow-derived DCs with recombinant IL-38 reduced cluster of differentiation 80 (CD80), CD86, and major histocompatibility complex (MHC) II expressions and decreased IL-1β, IL-6, and tumor necrosis factor (TNF)-α while increasing IL-10 secretion. The simultaneous culture of these semi-mature DCs with allogeneic CD4 T cells facilitated the production of Forkhead box protein P3-positive (Foxp3) Treg cells. A transcriptomic analysis revealed downregulation of the Chil3, Inhba, and Ctgf genes that are crucial for regulating inflammatory responses and cytokine-mediated signaling pathways in IL-38-treated DCs. In an animal model of asthma, IL38-DC treatment effectively decreased levels of an ovalbumin (OVA)-specific immunoglobulin E (IgE) antibody in serum, attenuated the severity of airway hyperresponsiveness, reduced the production of Th2-type cytokines (IL-4, IL-5, and IL-13) and proinflammatory cytokines (IL-6 and TNF-α) in bronchoalveolar lavage fluid, lowered expressions of the Th2-related cytokines IL-25 and thymic stromal-derived lymphopoietin (TSLP) by lung epithelial cells, and mitigated airway inflammation. Notably, enhanced expression of Foxp3 Treg cells was linked to increased mRNA levels of transforming growth factor (TGF)-β production in vivo. In conclusion, we comprehensively clarified the immunomodulatory effects of IL-38 on DCs and provide a new treatment with IL-38 genetically modified DCs for alleviating Th2-mediated allergic diseases.
过敏性哮喘是一种与异常免疫反应相关的慢性疾病，涉及针对过敏原的2型辅助性T（Th2）细胞。树突状细胞（DCs）在引导T细胞反应中起关键作用。调节性T（Treg）细胞具有抑制效应T细胞反应的能力，白细胞介素（IL）-38参与Treg细胞分化。在本研究中，我们探讨了IL-38对DCs激活和功能的影响，然后构建了一种过表达IL-38的腺病毒（Ad-IL38），通过Ad-IL38感染的DCs（IL38-DCs）的适应性转移来评估其在治疗小鼠过敏性哮喘中的有效性。用重组IL-38处理脂多糖（LPS）激活的骨髓来源的DCs可降低分化簇80（CD80）、CD86和主要组织相容性复合体（MHC）II的表达，并减少IL-1β、IL-6和肿瘤坏死因子（TNF）-α的产生，同时增加IL-10的分泌。将这些半成熟DCs与同种异体CD4 T细胞同时培养可促进叉头框蛋白P3阳性（Foxp3）Treg细胞的产生。转录组分析显示，在IL-38处理的DCs中，对调节炎症反应和细胞因子介导的信号通路至关重要的Chil3、Inhba和Ctgf基因表达下调。在哮喘动物模型中，IL38-DC治疗有效降低了血清中卵清蛋白（OVA）特异性免疫球蛋白E（IgE）抗体水平，减轻了气道高反应性的严重程度，减少了支气管肺泡灌洗液中Th2型细胞因子（IL-4、IL-5和IL-13）和促炎细胞因子（IL-6和TNF-α）的产生，降低了肺上皮细胞中Th2相关细胞因子IL-25和胸腺基质淋巴细胞生成素（TSLP）的表达，并减轻了气道炎症。值得注意的是，体内Foxp3 Treg细胞表达增强与转化生长因子（TGF）-β产生的mRNA水平增加有关。总之，我们全面阐明了IL-38对DCs的免疫调节作用，并为缓解Th2介导的过敏性疾病提供了一种用IL-38基因修饰的DCs的新治疗方法。
