Roles of TRAF3 in myeloid derived suppressor cells in chronic inflammation

摘要 髓系来源的抑制细胞(MDSCs)是慢性炎症的关键驱动力和强大的 免疫反应的抑制者。MDSCs的异常扩增和功能失调导致 许多涉及慢性炎症的人类疾病的发病机制。MDSC被认为是 这些疾病的重要治疗目标，目前正在加紧努力开发 抑制MDSCs扩张和阻断MDSCs功能的治疗。识别新的 因此，MDSCs的调节对于开发这种新的治疗方法至关重要。这项探索性的建议 目的：阐明一种新出现的MDSCs调控因子TRAF3的作用和信号机制。 多种免疫受体的信号转导。通过研究一种带有TRAF3的新小鼠模型 在髓系细胞(M-TRAF3-/-小鼠)中特异性缺失，我们最近发现TRAF3抑制慢性 炎症和感染可能通过控制MDSCs的扩张来实现。有力地佐证了我们的 发现，越来越多的证据表明，一些TRAF3直接利用免疫受体 规范MDSCs的扩张和/或抑制活动。尽管它可能很重要，但直接的角色 TRAF3在MDSCs中的表达仍不清楚。我们将解决当前在知识方面的这一重大差距 求婚。基于我们的新发现和初步结果，我们将检验TRAF3的中心假设 而依赖于TRAF3的信号通路直接控制着细胞的扩张和抑制功能 MDSCs，从而抑制慢性炎症。为了解决这个问题，我们建议在体外和体内补充 体内研究破译TRAF3介导的细胞和分子调控机制 MDSCs。重要的是，我们将确定免疫受体(S)发挥作用的内在信号通路 在MDSCs中TRAF3依赖的过程中起主导作用。我们的长期目标是获得新的见解 骨髓间充质干细胞的生理调控机制及其介导的慢性炎症和 免疫抑制在疾病发病机制中的作用。这些知识将为发展 在MDSCs中操纵TRAF3信号通路的创新治疗策略 慢性炎症性疾病、癌症、自身免疫性疾病和慢性传染病。

Summary Myeloid-derived suppressor cells (MDSCs) are crucial drivers of chronic inflammation and potent suppressors of immune responses. Aberrant expansion and dysregulated functions of MDSCs contribute to the pathogenesis of numerous human diseases involving chronic inflammation. MDSCs are recognized as an important therapeutic target for these diseases, and Intensive efforts are currently directed at developing therapies to inhibit the expansion of MDSCs and to block the functions of MDSCs. Identification of new regulators of MDSCs is thus critical for the development of such novel therapies. This exploratory proposal aims to elucidate the roles and signaling mechanisms of a novel emerging regulator of MDSCs, TRAF3, a signal transducer of a variety of immune receptors. By examining a new mouse model that has TRAF3 specifically deleted in myeloid cells (M-TRAF3-/- mice), we recently found that TRAF3 inhibits chronic inflammation and infection likely through controlling the expansion of MDSCs. In strong corroboration of our findings, increasing evidence indicates that a number of TRAF3-employing immune receptors directly regulate the expansion and/or suppressive activities of MDSCs. Despite its likely importance, the direct roles of TRAF3 in MDSCs remain unknown. We will address this significant gap in knowledge in the current proposal. Based on our new findings and preliminary results, we will test the central hypothesis that TRAF3 and TRAF3-dependent signaling pathways directly control the expansion and suppressive functions of MDSCs, thereby inhibiting chronic inflammation. To address this, we propose complementary in vitro and in vivo studies to decipher the cellular and molecular mechanisms underlying TRAF3-mediated regulation of MDSCs. Importantly, we will identify the intrinsic signaling pathways of immune receptor(s) that play dominant roles in the TRAF3-dependent processes in MDSCs. Our long-term goal is to gain new insights into the regulatory mechanisms of MDSC physiology as well as MDSC-mediated chronic inflammation and immunosuppression in disease pathogenesis. Such knowledge will pave the way towards developing innovative therapeutic strategies to manipulate TRAF3 signaling pathways in MDSCs for the treatment of chronic inflammatory diseases, cancers, autoimmune diseases, and chronic infectious diseases.