Olfactory ecto-mesenchymal stem cell-derived exosomes ameliorate murine Sjögren's syndrome by modulating the function of myeloid-derived suppressor cells.
Olfactory ecto-mesenchymal stem cell-derived exosomes ameliorate murine Sjögren's syndrome by modulating the function of myeloid-derived suppressor cells.
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嗅觉外间充质干细胞来源的外泌体通过调节骨髓源性抑制细胞的功能改善小鼠干燥综合征
DOI：
10.1038/s41423-020-00587-3
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发表时间：
2021-03
影响因子：
24.1
通讯作者：
Lu L
中科院分区：
文献类型：
--
作者：
Rui K;Hong Y;Zhu Q;Shi X;Xiao F;Fu H;Yin Q;Xing Y;Wu X;Kong X;Xu H;Tian J;Wang S;Lu L
干燥综合征（SS）是一种全身性自身免疫性疾病，其特征是唾液腺和泪腺出现进行性炎症和组织损伤。我们之前的研究表明，在干燥综合征患者以及实验性干燥综合征（ESS）小鼠的疾病进展过程中，髓源性抑制细胞（MDSCs）的免疫抑制功能受损，但恢复MDSCs的功能是否能有效改善ESS的发展仍不清楚。在本研究中，我们发现小鼠嗅外间充质干细胞衍生的外泌体（OE - MSC - Exos）通过上调精氨酸酶表达以及提高活性氧（ROS）和一氧化氮（NO）水平，显著增强了MDSCs的抑制功能。此外，通过静脉注射OE - MSC - Exos进行治疗，显著减轻了ESS小鼠的疾病进展并恢复了MDSC功能。从机制上讲，OE - MSC - Exo分泌的白细胞介素 - 6（IL - 6）激活了MDSCs中的Jak2/Stat3通路。此外，OE - MSC - Exos中丰富的S100A4是通过Toll样受体4（TLR4）信号传导介导MDSCs内源性产生IL - 6的关键因素，这表明了IL - 6对MDSC功能调节的自分泌途径。综上所述，我们的研究结果表明，OE - MSC - Exos具有通过增强MDSCs的免疫抑制功能来减轻ESS进展的治疗潜力，可能构成治疗干燥综合征及其他自身免疫性疾病的一种新策略。
Sjögren’s syndrome (SS) is a systemic autoimmune disease characterized by progressive inflammation and tissue damage in salivary glands and lacrimal glands. Our previous studies showed that myeloid-derived suppressor cells (MDSCs) exhibited impaired immunosuppressive function during disease progression in patients with SS and mice with experimental Sjögren’s syndrome (ESS), but it remains unclear whether restoring the function of MDSCs can effectively ameliorate the development of ESS. In this study, we found that murine olfactory ecto-mesenchymal stem cell-derived exosomes (OE-MSC-Exos) significantly enhanced the suppressive function of MDSCs by upregulating arginase expression and increasing ROS and NO levels. Moreover, treatment with OE-MSC-Exos via intravenous injection markedly attenuated disease progression and restored MDSC function in ESS mice. Mechanistically, OE-MSC-Exo-secreted IL-6 activated the Jak2/Stat3 pathway in MDSCs. In addition, the abundant S100A4 in OE-MSC-Exos acted as a key factor in mediating the endogenous production of IL-6 by MDSCs via TLR4 signaling, indicating an autocrine pathway of MDSC functional modulation by IL-6. Taken together, our results demonstrated that OE-MSC-Exos possess therapeutic potential to attenuate ESS progression by enhancing the immunosuppressive function of MDSCs, possibly constituting a new strategy for the treatment of Sjögren’s syndrome and other autoimmune diseases.
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