Stimulation of mesenchymal stromal cells (MSCs) via TLR3 reveals a novel mechanism of autocrine priming
Stimulation of mesenchymal stromal cells (MSCs) via TLR3 reveals a novel mechanism of autocrine priming
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DOI：
10.1096/fj.14-250159
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发表时间：
2014-09-01
期刊：
影响因子：
4.8
通讯作者：
Brandau, Sven
中科院分区：
文献类型：
--
作者：
Dumitru, Claudia A.;Hemeda, Hatim;Brandau, Sven
间充质干/基质细胞（MSC）正在成为先天性和适应性免疫的重要调节因子。在这种情况下，已经描述了MSC的促炎和抗炎作用。目前，介导这种功能可塑性的机制尚不清楚。在这里，我们研究了从人鼻粘膜分离的MSC（nmMSC）的炎症反应后的挑战与不同的Toll样受体（TLR）配体。我们发现，与其他TLR配体相比，TLR 3配体诱导nmMSCs释放最强的促炎细胞因子[白细胞介素（IL）-6和IL-8]和I型干扰素。值得注意的是，TLR 3配体触发了双相细胞因子反应，I型干扰素在刺激后4 h出现早期峰值，促炎细胞因子在刺激后24 h出现晚期释放。虽然早期干扰素反应受到直接刺激，促炎反应是由早期细胞因子反应期间释放的因子调节的，其随后增强了对TLR 3连接的敏感性，并扩增了IL-6和IL-8的产生，但不扩增干扰素的产生。综上所述，我们的研究结果表明，TLR 3配体以时间依赖性方式抑制MSC的炎症表型。因此，我们的研究提出了一种新的模型，有助于解释MSC在炎症和免疫调节中惊人的二分功能。
Mesenchymal stem/stromal cells (MSCs) are emerging as important regulators of innate and adaptive immunity. In this context, both proinflammatory and anti-inflammatory effects have been described for MSCs. The mechanisms mediating this functional plasticity are poorly characterized at present. Here, we investigated the inflammatory responses of MSCs isolated from human nasal mucosa (nmMSCs) upon challenge with different Toll-like receptor (TLR) ligands. We found that TLR3 ligands induced the strongest release of both proinflammatory cytokines [interleukin (IL)-6 and IL-8] and type I interferon by nmMSCs compared with other TLR ligands. Notably, TLR3 ligands triggered a biphasic cytokine response, with an early peak of type I interferon at 4 h poststimulation and a late release of proinflammatory cytokines at 24 h poststimulation. While the early interferon response was subject to direct stimulation, the proinflammatory response was regulated by factors released during the early cytokine response, which subsequently enhanced sensitivity to TLR3 ligation and amplified the production of IL-6 and IL-8 but not that of interferon. Taken together, our findings indicate that TLR3 ligands polarize the inflammatory phenotype of MSCs in a time-dependent manner. Thus, our study proposes a novel model that helps to explain the strikingly dichotomous functionality of MSCs in inflammation and immunoregulation.