Myeloid reprogramming in response to acute radiation tissue damage

响应急性辐射组织损伤的骨髓重编程

基本信息

批准号：
10375367
负责人：
Dorthe Schaue
金额：
$ 34.97万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10375367
关键词：
Acute Address Adoptive Cell Transfers Adoptive Transfer Affect Animal Model Antibodies Appearance Automobile Driving Back Biological Markers Blood Bone Marrow Brain CCL2 gene Cells Chest Chronic Color Complex Dose Endotoxins Environment Equilibrium Exhibits Exposure to Fibrosis Flow Cytometry Genetic Goals Growth Factor HMGB1 gene Heart Hematopoiesis Hematopoietic Hour Human Immune Immune System Diseases Immune response In Vitro Infiltration Inflammation Inflammatory Inflammatory Response Interleukin-6 Intestines Limb structure Lung Lymphopoiesis Mediating Molecular Mus Myelogenous Myeloid Cells Myeloid-derived suppressor cells Myelopoiesis Normal tissue morphology Organ Pathway interactions Patients Pattern Peripheral Pharmaceutical Preparations Phenotype Play Process Proto-Oncogene Protein c-kit Radiation Radiation Oncology Radiation Toxicity Radiation exposure Radiation induced damage Radiation therapy Reagent Recovery Regenerative capacity Role Serum Severities Shapes Signal Pathway Signal Transduction Skin Spleen System TLR1 gene Testing Time Tissues Trauma Uncertainty Whole-Body Irradiation cytokine granulocyte in vivo irradiation loss of function mindfulness monocyte mouse model novel prevent programmed cell death ligand 1 programmed cell death protein 1 radiation mitigator radiation response radiation-induced tissue damage response side effect stem cells tool tumor

项目摘要

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.

我们发现继全身和骨髓细胞之后出现了一种新的骨髓细胞亚群局部照射可高水平表达粒细胞 (Ly6G) 和单核细胞 (Ly6C) 谱系标记。这种不成熟的表型通常在基线时的外周器官中并不明显，而是从骨骼中动员出来骨髓骨髓红系祖细胞。它们的表型表明它们可能是粒细胞衍生的骨髓抑制细胞，以及它们共表达 PDL-1、PD-1 和 CD39 的情况。我们假设他们是一种内源性机制，可最大限度地减少辐射引起的组织损伤造成的附带损害，炎。重要的是，该子集的消耗增加了造血急性辐射的脆弱性小鼠综合症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骨髓细胞的命运和功能以及它们在急性和慢性疾病中所发挥的作用动物模型中的辐射组织损伤。我们注意到骨髓细胞往往对快速变化的环境及其表型和功能相应地适应；与可塑性是这个血统的标志。我们的假设是这些细胞感知损伤并做出反应- 辐射暴露后释放的相关分子和细胞因子，它们反馈到骨髓驱动炎症和骨髓谱系重编程的自我维持循环，从而扭曲免疫平衡从淋巴细胞生成转向骨髓生成。从长远来看，持续性骨髓细胞倾斜会影响造血功能，或许还会影响其他器官的功能。最有可能调解此事的罪魁祸首辐射引起的快速骨髓细胞激增是 IL-6，但其他因素可能也很重要。我们将追求这些使用多色流式细胞术、Ly6G 消耗抗体、过继细胞转移和丢失工具箱的途径功能遗传小鼠模型将使我们能够精细剖析这种反应在急性和晚期的作用辐射损伤。作为研究的一部分，我们将验证这些细胞是否具有固有的辐射缓解能力能力。最后，这些细胞会全身持续存在，并可能导致正常组织延迟和肿瘤对放射治疗的反应。因此，我们将确定它们如何塑造持久的炎症状态和免疫功能障碍。通过这些研究，我们希望更深入地了解辐射组织之间的相互作用损伤、免疫反应和恢复过程，最终目标是重新编程骨髓系统更好地帮助局部和全身辐射暴露后平衡的正常组织恢复。