Defining Protective Responses in Hematopoietic Cells Mediated by STAT3 Anti-Inflammatory Activity

定义 STAT3 抗炎活性介导的造血细胞保护反应

• 批准号: 9906160
• 负责人: Stephanie S Watowich
• 金额: $ 42.94万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-21 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9906160
• 关键词: Acute Myelocytic Leukemia; Adult; Agonist; Animals; Anti-Inflammatory Agents; Autoimmune Process; Autoimmunity; Bacterial Infections; Blood Cells; Bone Marrow; Bone Marrow Transplantation; Cell Lineage; Cells; Chimera organism; Chronic; Conditioned Reflex; Cues; DNA Damage; Development; Disease; Dysmyelopoietic Syndromes; Event; Excision; Exhibits; Foundations; Gene Expression; Gene Expression Profiling; Genetic Transcription; Goals; Health; Hematological Disease; Hematopoiesis; Hematopoietic; Hematopoietic System; Hematopoietic stem cells; Homeostasis; Human; Immune System Diseases; Immune system; Immunity; Immunologic Deficiency Syndromes; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Job' s Syndrome; Knowledge; Learning; Link; Lymphoid; Lymphopoiesis; MAP Kinase Gene; Malignant Neoplasms; Mediating; Medical; Molecular; Multipotent Stem Cells; Mus; Myelogenous; Myeloid Cells; Output; Pancytopenia; Pathway interactions; Peripheral; Physiological; Population; Prevention; Production; Regulation; Research; Role; Signal Transduction; Stat3 protein; Stimulus; TLR2 gene; TLR4 gene; TRAF6 gene; Testing; Toll-like receptors; Transcription Repressor; Transgenic Organisms; Ubiquitin-Conjugating Enzymes; Virus Diseases; Work; base; clinically relevant; cytokine; fighting; functional disability; gene repression; genome-wide; improved; insight; mutant; novel; pathogen; preservation; progenitor; response; restraint; stem; stem cells; transcription factor

PROJECT SUMMARY/ABSTRACT The hematopoietic system is the foundation of the inflammatory response. Hematopoietic stem cells and multipotent progenitors (collectively termed HSPCs) residing in adult bone marrow generate inflammatory myeloid and lymphoid populations. HSPCs also respond to pathogen-associated inflammatory stimuli by adjusting the output of cells required to fight infection. HSPC activity is unfortunately co-opted in chronic inflammatory conditions. These induce HSPC deregulation, loss of long-term stem cell repopulating function, DNA damage, and myeloid-skewed hematopoiesis. In humans, chronic inflammation is linked with bone marrow failure, myelodysplastic syndrome, and acute myeloid leukemia. An important gap in knowledge is how the hematopoietic system is protected from the harmful effects of inflammation. By investigating this question, we discovered a key role for the cytokine-activated transcriptional regulator STAT3; specifically, our results suggest STAT3 anti-inflammatory activity is necessary to preserve HSPCs and lineage-balanced hematopoiesis. We showed previously that STAT3 anti-inflammatory activity is mediated by transcriptional repression of Ube2n, encoding Ubc13, an E2 ubiquitin-conjugating enzyme that activates TRAF6 and NF- κB/MAPK signaling downstream of Toll-like receptors (TLRs) (e.g., TLR2, TLR4). We found hematopoietic- restricted Stat3-deficiency leads to bone marrow failure, HSPC loss, myeloid-skewed hematopoiesis and increased progenitor pro-inflammatory signaling. Strikingly, concomitant removal of Ube2n from Stat3-deficient hematopoietic cells enables hematopoietic activity, suggesting STAT3 restraint of Ubc13 is required to maintain functional HSPCs. Thus, we hypothesize STAT3 has a central role in protecting HSPCs from inflammation-induced damage via modulation of Ubc13. To test this (Aim 1), we will investigate the role for STAT3 in protecting hematopoietic function in inflammation. Using mixed bone marrow chimeras, we will determine roles for STAT3 and Ubc13 in hematopoietic responses to inflammation; we will investigate STAT3- activating cytokines and producer populations in bone marrow; and we will test the requirement for STAT3 transcriptional activity in HSPCs during inflammation using a transgenic strain expressing a transcriptionally defective STAT3 mutant. In Aim 2, we will delineate molecular pathways by which STAT3 protects HSPCs from inflammation-induced damage. We will determine roles for STAT3 and Ubc13 in protecting HSPCs from DNA damage and loss of quiescence during inflammation, and we will determine STAT3- and Ubc13- genome- wide transcriptional responses in HSPCs in homeostasis and inflammation. We anticipate this project will provide unprecedented insight into intrinsic HSPCs protective mechanisms, fundamental information that will move the field forward to an improved understanding of immune system regulation during inflammation.

项目摘要/摘要 造血系统是炎症反应的基础。造血干细胞和 居住在成人骨髓中的多能祖细胞(统称为HSPC)会产生炎症反应 髓系和淋巴系种群。HSPC还通过以下方式对病原体相关的炎症刺激做出反应 调整抵抗感染所需的细胞产量。HSPC活动不幸地被慢性疾病所增选 炎症状态。这些导致HSPC去调控，失去长期干细胞再繁殖功能， DNA损伤和髓系粒细胞倾斜的造血。在人类中，慢性炎症与骨骼有关 骨髓衰竭、骨髓增生异常综合征和急性髓系白血病。知识中的一个重要差距是如何 造血系统受到保护，免受炎症的有害影响。通过调查这个问题， 我们发现了细胞因子激活的转录调节因子STAT3的关键作用；具体地说，我们的结果 提示STAT3抗炎活性对于保持HSPC和谱系平衡是必要的 造血术。我们以前已经证明，STAT3的抗炎活性是通过转录介导的 抑制编码UBC13的Ube2n，UBC13是一种激活TRAF6和NF-2的E2泛素结合酶 Toll样受体(TLRs)下游的κB/MAPK信号转导通路。我们发现了造血功能- 限制性STAT3缺乏会导致骨髓衰竭、HSPC丢失、髓系偏斜的造血和 祖细胞致炎信号增强。引人注目的是，伴随着从STAT3缺陷中去除Ube2n 造血细胞能够促进造血活性，这表明需要抑制UBC13的STAT3 维护正常运行的HSPC。因此，我们假设STAT3在保护HSPC免受 炎症诱导的损伤通过调节UBC13。为了测试这一点(目标1)，我们将调查 STAT3在炎症中保护造血功能的作用。使用混合骨髓嵌合体，我们将 确定STAT3和UBC13在炎症造血反应中的作用；我们将研究STAT3- 激活骨髓中的细胞因子和生产者群体；我们将测试对STAT3的需求 利用表达转录因子基因的转基因株研究炎症期间HSPC的转录活性 有缺陷的STAT3突变体。在目标2中，我们将描述STAT3保护HSPC的分子途径 不受炎症引起的损伤。我们将确定STAT3和UBC13在保护HSPC免受 在炎症过程中DNA损伤和静止的丧失，我们将确定STAT3和UBC13基因组- 动态平衡和炎症中HSPC的广泛转录反应。我们预计这个项目将 提供对HSPC内在保护机制的前所未有的洞察，基本信息将 推动这一领域向前发展，以更好地理解炎症期间的免疫系统调节。