Myeloid reprogramming in response to acute radiation tissue damage

我们发现，在全身和 局部照射，高水平表达粒细胞(Ly6G)和单核细胞(Ly6C)谱系标志。 这种未成熟的表型在基线时在外周器官中通常不明显，但从骨骼中动员起来 骨髓红系祖细胞。它们的表型表明它们可能是粒细胞来源的。 髓系抑制细胞及其共表达的PDL-1、PD-1和CD39。我们假设他们 是一种内源性机制，可将辐射引起的组织损伤的附带损害降至最低 发炎。重要的是，这一亚群的耗尽增加了对造血急性辐射的易感性。 小鼠的症状，并消除了我们测试过的辐射缓解药物的作用。 我们的目标是阐明这些髓系细胞的命运和功能，以及它们在急性和慢性疾病中所起的作用。 动物模型中的放射性组织损伤。我们注意到，髓系细胞往往对 快速变化的环境，它们的表型和功能也相应地适应； 可塑性是这一血统的标志。我们的假设是这些细胞感知并对损伤做出反应- 相关分子和细胞因子在辐射暴露后释放，它们反馈给 骨髓驱动炎症和髓系重编程的自我维持循环 免疫平衡从淋巴细胞生成转向骨髓生成。从长远来看，持久性髓系 偏斜会影响造血，可能还会影响其他器官的功能。最有可能调解这一事件的罪魁祸首 辐射引起的快速髓系激增是IL-6，但其他因素可能也很重要。我们将致力于实现这些目标 途径采用工具箱多色流式细胞术、Ly6G耗竭抗体、过继细胞转移和丢失 这将使我们能够精细地剖析这种反应在急性和晚期中的作用 辐射损伤。作为研究的一部分，我们将验证这些细胞是否具有内在的辐射缓解作用 能力。最后，这些细胞在系统中持续存在，可能对延迟的正常组织和 肿瘤对放射治疗的反应。因此，我们将确定它们可能会如何形成持久性 炎症状态和免疫功能障碍。 通过这些研究，我们希望对辐射组织之间的相互作用有更深入的了解。 损伤、免疫反应和恢复过程，最终目标是重新编程髓系 系统，以更好地帮助平衡的正常组织恢复后，局部和全身辐射暴露。

We have discovered the striking emergence of a novel subpopulation of myeloid cells after whole body and local irradiation that expresses both granulocytic (Ly6G) and monocytic (Ly6C) lineage markers at high levels. This immature phenotype is not normally evident in peripheral organs at baseline but is mobilized from bone marrow myeloerythroid progenitor cells. Their phenotype suggests that they may be granulocyte-derived myeloid suppressor cells, as does their co-expression of PDL-1, PD-1, and CD39. We hypothesize that they are an endogenous mechanism to minimize collateral damage from radiation-induced tissue damage and inflammation. Importantly, depletion of this subset increases vulnerability to hematopoietic acute radiation syndrome in mice and obliterates the action of radiation mitigator drugs that we have tested. Our goal is to illuminate the fate and function of these myeloid cells and the role they play in acute and chronic radiation tissue damage in animal models. We are mindful that myeloid cells tend to be exquisitely sensitive to rapidly changing environments and that their phenotype and function adapt accordingly; in keeping with the plasticity that is a hallmark of this lineage. Our hypothesis is that these cells sense and respond to damage- associated molecules and cytokines released in the aftermath of radiation exposure, that they feed back to the bone marrow driving self-sustaining loops of inflammation and myeloid lineage reprogramming which skews the immune balance away from lymphopoiesis and towards myelopoiesis. In the long term, persistent myeloid skewing affects hematopoiesis and perhaps function of other organs. The most likely culprit for mediating this rapid radiation-induced myeloid surge is IL-6, but other factors are probably important. We will pursue these avenues using a tool box of multi-color flow cytometry, Ly6G-depleting antibody, adoptive cell transfer and loss of function genetic mouse models that will allow us to finely dissect the role of this response in acute and late radiation damage. As part of the study, we will verify if these cells have inherent radiation mitigating capabilities. Finally, these cells persist systemically and probably contribute to delayed normal tissue and tumor responses to radiation therapy. We will therefore determine how they might shape persistent inflammatory states and immune dysfunction. With these studies we hope to gain a deeper understanding of the interactions between radiation tissue damage, immune responses and the recovery processes with the ultimate goal of reprogramming the myeloid system to better aid balanced normal tissue recovery after localized and whole body radiation exposures.