S100A4 and Uric Acid Promote Mesenchymal Stromal Cell Induction of IL-10+/IDO+ Lymphocytes
S100A4 and Uric Acid Promote Mesenchymal Stromal Cell Induction of IL-10+/IDO+ Lymphocytes
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DOI：
10.4049/jimmunol.1303144
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发表时间：
2014-06-15
影响因子：
4.4
通讯作者：
Lotfi, Ramin
中科院分区：
文献类型：
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作者：
Eisenbacher, Judith Luiza;Schrezenmeier, Hubert;Lotfi, Ramin
简单的应激或坏死性细胞死亡，随后释放损伤相关分子模式（DAMP）是大多数晚期肿瘤的特征。肿瘤微环境中的DAMP刺激肿瘤相关细胞，包括树突状细胞和间充质基质细胞（MSC）。肿瘤浸润MSC的存在与肿瘤进展和转移相关。氧化坏死物质失去其对MSC的刺激能力。作为DAMP，S100 A4对氧化敏感，而尿酸（UA）主要作为抗氧化剂。我们分别和组合测试了这两种生物部分对MSC的活性。与坏死的肿瘤材料相似，S100 A4和UA都剂量依赖性地诱导MSC的趋化性，当组合时具有协同效应。替代UA，替代抗氧化剂（维生素C、DTT和N-乙酰半胱氨酸）也以协同方式增强S100 A4的趋化活性。这就强调了普遍获得服务的减少潜力，至少部分地是所观察到的协同作用的原因。关于MSC增殖，S100 A4和UA均抑制MSC而不改变存活或诱导向脂肪细胞、骨细胞或软骨细胞的分化。在S100 A4或UA的存在下，MSC获得免疫抑制能力并稳定诱导表达IL-10和IDO的淋巴细胞，这些淋巴细胞在增殖后保持其表型。因此，我们已经证明，S100 A4和UA都作为DAMP，因此，可能在促进MSC相关免疫调节的某些方面发挥关键作用。我们的研究结果对靶向肿瘤微环境的治疗方法和解决肿瘤微环境中非程序性细胞死亡的免疫抑制性质具有意义。
Simple stress or necrotic cell death with subsequent release of damage-associated molecular patterns (DAMPs) is a characteristic feature of most advanced tumors. DAMPs within the tumor microenvironment stimulate tumor-associated cells, including dendritic cells and mesenchymal stromal cells (MSCs). The presence of tumor-infiltrating MSCs is associated with tumor progression and metastasis. Oxidized necrotic material loses its stimulatory capacity for MSCs. As a DAMP, S100A4 is sensitive to oxidation whereas uric acid (UA) acts primarily as an antioxidant. We tested these two biologic moieties separately and in combination for their activity on MSCs. Similar to necrotic tumor material, S100A4 and UA both dose-dependently induced chemotaxis of MSCs with synergistic effects when combined. Substituting for UA, alternative antioxidants (vitamin C, DTT, and N-acetylcysteine) also enhanced the chemotactic activity of S100A4 in a synergistic manner. This emphasizes the reducing potential of UA being, at least in part, responsible for the observed synergy. With regard to MSC proliferation, both S100A4 and UA inhibited MSCs without altering survival or inducing differentiation toward adipo-, osteo-, or chondrocytes. In the presence of S100A4 or UA, MSCs gained an immunosuppressive capability and stably induced IL-10-and IDO-expressing lymphocytes that maintained their phenotype following proliferation. We have thus demonstrated that both S100A4 and UA act as DAMPs and, as such, may play a critical role in promoting some aspects of MSC-associated immunoregulation. Our findings have implications for therapeutic approaches targeting the tumor microenvironment and addressing the immunosuppressive nature of unscheduled cell death within the tumor microenvironment.