Low-dose 5-fluorouracil ameliorates Th2 responses through the induction of apoptotic cell death of lung monocyte-derived dendritic cells in asthma
Low-dose 5-fluorouracil ameliorates Th2 responses through the induction of apoptotic cell death of lung monocyte-derived dendritic cells in asthma
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DOI：
10.1016/j.biopha.2022.113875
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发表时间：
2022-10-19
影响因子：
7.5
通讯作者：
Nie，Hanxiang
中科院分区：
文献类型：
--
作者：
Deng，Nishan;Zuo，Xiaoshu;Nie，Hanxiang
5-氟尿嘧啶（5-FU）是嘧啶的类似物，已被证明具有抗肿瘤和免疫调节作用。然而，5-FU在调节哮喘（一种与T辅助细胞2 （Th2）反应相关的炎症性疾病）中的作用尚不清楚。在这里，我们确定了低剂量5-FU对哮喘Th2细胞反应的调节作用，并通过过继细胞转移和体外培养实验描述了其潜在机制。我们的数据表明，低剂量5-FU治疗不仅可以抑制过敏原致敏小鼠的哮喘诱导，还可以消除已建立疾病小鼠哮喘的主要特征。我们发现5-FU治疗哮喘的这种保护作用伴随着哮喘小鼠肺单核细胞来源的树突状细胞（moDCs）数量的减少。此外，我们发现过继转移modc逆转了5-FU治疗对哮喘小鼠Th2细胞反应的抑制作用。令人惊讶的是，5-FU治疗并没有抑制哮喘小鼠肺中moDCs的表面成熟标记物和免疫原性。相反，它在体外和体内均可诱导小鼠moDCs的凋亡细胞死亡。除了对小鼠moDCs的影响外，我们还观察到低剂量5-FU处理可以诱导体外培养的人外周血单核细胞moDCs的凋亡细胞死亡。总之，我们的研究结果表明，低剂量5-FU改善Th2细胞反应，这可能至少部分与哮喘moDCs诱导凋亡细胞死亡有关。
5-Fluorouracil (5-FU) is an analog of pyrimidine and has been shown to display antitumor and immunomodulatory effects. However, the impacts of 5-FU in regulating asthma, an inflammatory disease associated with T helper cell 2 (Th2) responses, remain unclear. Here, we determine the modulatory effects of low-dose 5-FU on Th2 cell responses in asthma and delineate the underlying mechanisms using adoptive cell transfer and in vitro culture experiments. Our data show that low-dose 5-FU treatment not only inhibits the induction of asthma in allergen-sensitized mice but also abrogates the major features of asthma in mice with established disease. We find that this protection of 5-FU treatment against asthma is accompanied by a decrease in the number of lung monocyte-derived dendritic cells (moDCs) in the asthmatic murine. Furthermore, we show that adoptive transfer of moDCs reverses the inhibitory effects of 5-FU treatment on Th2 cell responses in asthmatic mice. Surprisingly, 5-FU treatment does not suppress surface maturation markers and immunogenicity of moDCs in the lungs of asthmatic mice. Instead, it induces apoptotic cell death of mouse moDCs both in vitro and in vivo. In addition to its impact on mouse moDCs, we observe that low-dose 5-FU treatment can induce apoptotic cell death of human moDCs derived from peripheral blood mononuclear cells in vitro. Together, our findings reveal that low-dose 5-FU ameliorates Th2 cell responses, which may be at least partially related to the induction of apoptotic cell death of moDCs in asthma.