Tumor Necrosis Factor-α Blocks Differentiation and Enhances Suppressive Activity of Immature Myeloid Cells during Chronic Inflammation
Tumor Necrosis Factor-α Blocks Differentiation and Enhances Suppressive Activity of Immature Myeloid Cells during Chronic Inflammation
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DOI：
10.1016/j.immuni.2013.02.007
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发表时间：
2013-03-21
期刊：
影响因子：
32.4
通讯作者：
Baniyash, Michal
中科院分区：
文献类型：
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作者：
Sade-Feldman, Moshe;Kanterman, Julia;Baniyash, Michal
肿瘤坏死因子-a （tnf - α）浓度升高在以慢性炎症为特征的病理中被检测到。tnf - α是否在操纵宿主免疫系统产生免疫抑制环境中发挥作用，这是持续慢性炎症的典型特征，目前尚不清楚。在这里，我们发现tnf - α在慢性炎症中表现出双重功能：主要通过S100A8和S100A9炎症蛋白及其相应受体（RAGE）阻止未成熟髓源性抑制细胞（MDSCs）的分化，并增强MDSCs的抑制活性。这些功能导致体内T细胞和NK细胞功能紊乱，并伴有T细胞抗原受体zeta链下调。此外，在早期慢性炎症阶段给予依那西普（tnf - α拮抗剂）可降低MDSCs的抑制活性，增强其向树突状细胞和巨噬细胞的成熟，从而恢复体内免疫功能和恢复zeta链表达。因此，TNF在促进慢性炎症期间产生的免疫抑制环境中起着重要作用。
Elevated concentrations of tumor necrosis factor-a (TNF-alpha) are detected in pathologies characterized by chronic inflammation. Whether TNF-alpha plays a role in manipulating the host's immune system toward generating an immunosuppressive milieu, typical of ongoing chronic inflammation, is unclear. Here we showed that TNF-alpha exhibited a dual function during chronic inflammation: arresting differentiation of immature myeloid-derived suppressor cells (MDSCs) primarily via the S100A8 and S100A9 inflammatory proteins and their corresponding receptor (RAGE) and augmenting MDSC suppressive activity. These functions led to in vivo T and NK cell dysfunction accompanied by T cell antigen receptor zeta chain downregulation. Furthermore, administration of etanercept (TNF-alpha antagonist) during early chronic inflammatory stages reduced MDSCs' suppressive activity and enhanced their maturation into dendritic cells and macrophages, resulting in the restoration of in vivo immune functions and recovery of zeta chain expression. Thus, TNF has a fundamental role in promoting an immunosuppressive environment generated during chronic inflammation.