Medical Microbiology and Hygiene, Centre for Infectious Diseases, University Hospital Heidelberg, Heidelberg, Germany.
German Center for Infection Research (DZIF), Brunswick, Germany.
Front Immunol. 2018 Jun 18;9:1224. doi: 10.3389/fimmu.2018.01224. eCollection 2018.
Antigen-presenting cells (APCs) regulate the balance of our immune response toward microbes. Whereas immunogenic APCs boost inflammation and activate lymphocytes, the highly plastic cells can switch into a tolerogenic/suppressive phenotype that dampens and resolves the response. Thereby the initially mediated inflammation seems to prime the switch of APCs while the strength of activation determines the grade of the suppressive phenotype. Recently, we showed that pathogen recognition receptor-mediated pro-inflammatory cytokines reprogram differentiating human blood monocytes toward an immunosuppressive phenotype through prolonged activation of signal transducer and activator of transcription (STAT) 3. The TLR7/8 ligand R848 (Resiquimod) triggers the high release of cytokines from GM-CSF/IL-4-treated monocytes. These cytokines subsequently upregulate T cell suppressive factors, such as programmed death-ligand 1 (PD-L1) and indolamin-2,3-dioxygenase (IDO) through cytokine receptor-mediated STAT3 activation. Here, we reveal an essential role for the microRNA (miR, miRNA) hsa-miR-99b/let-7e/miR-125a cluster in stabilizing the suppressive phenotype of R848-stimulated APCs on different levels. On the one hand, the miR cluster boosts R848-stimulated cytokine production through regulation of MAPkinase inhibitor Tribbles pseudokinase 2, thereby enhancing cytokine-stimulated activation of STAT3. One the other hand, the STAT3 inhibitor suppressor of cytokine signaling-1 is targeted by the miR cluster, stabilizing the STAT3-induced expression of immunosuppressive factors PD-L1 and IDO. Finally, hsa-miR-99b/let-7e/miR-125a cluster regulates generation of the suppressive tryptophan (Trp) metabolite kynurenine by targeting the tryptophanyl-tRNA synthetase WARS, the direct competitor of IDO in terms of availability of Trp. In summary, our results reveal the hsa-miR-99b/let-7e/miR-125a cluster as an important player in the concerted combination of mechanisms that stabilizes STAT3 activity and thus regulate R848-stimulated suppressive APCs.
抗原呈递细胞 (APCs) 调节我们对微生物的免疫反应平衡。虽然免疫原性 APC 会增强炎症并激活淋巴细胞，但这些高度可塑性的细胞可以转变为耐受性/抑制性表型，从而减轻和解决反应。因此，最初介导的炎症似乎启动了 APC 的转变，而激活的强度决定了抑制性表型的程度。最近，我们表明，病原体识别受体介导的促炎细胞因子通过延长信号转导和转录激活因子 (STAT) 3 的激活，将分化中的人血单核细胞重新编程为免疫抑制表型。TLR7/8 配体 R848（Resiquimod）触发 GM-CSF/IL-4 处理的单核细胞中细胞因子的大量释放。这些细胞因子随后通过细胞因子受体介导的 STAT3 激活上调 T 细胞抑制因子，如程序性死亡配体 1 (PD-L1) 和吲哚胺 2,3-双加氧酶 (IDO)。在这里，我们揭示了 microRNA (miRNA，miRNA) hsa-miR-99b/let-7e/miR-125a 簇在稳定 R848 刺激的 APC 不同水平的抑制表型方面的重要作用。一方面，该 miRNA 簇通过调节丝裂原活化蛋白激酶抑制剂 Tribbles 假激酶 2 促进 R848 刺激的细胞因子产生，从而增强细胞因子刺激的 STAT3 激活。另一方面，STAT3 抑制剂细胞因子信号转导抑制因子-1 是该 miRNA 簇的靶标，稳定 STAT3 诱导的免疫抑制因子 PD-L1 和 IDO 的表达。最后，hsa-miR-99b/let-7e/miR-125a 簇通过靶向色氨酸 tRNA 合成酶 WARS 调节抑制性色氨酸 (Trp) 代谢产物犬尿氨酸的生成，WARS 是 IDO 在 Trp 可用性方面的直接竞争物。总之，我们的结果揭示了 hsa-miR-99b/let-7e/miR-125a 簇作为稳定 STAT3 活性并调节 R848 刺激的抑制性 APC 的协同组合机制中的重要参与者。
