Effects of Microbial Exposure on Myelopoiesis

微生物暴露对骨髓生成的影响

基本信息

批准号：
7895442
负责人：
Helen S Goodridge
金额：
$ 20.63万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-18 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7895442
关键词：
Affect Agonist Cell physiology Cells Clinical Commit Data Detection Disease Dose Evolution Excision Exhibits Exposure to Family Future Generations Goals Hematopoietic Hematopoietic stem cells Immune Immune response Immune system In Vitro Infection Infectious Agent Inflammation Inflammation Mediators Inflammatory Interleukin-6 Invaded Investigation Leukocytes Ligands Ligation Microbe Myelogenous Myeloid Cells Myelopoiesis Oxygen Peripheral Phagocytes Play Population Predisposition Process Production Receptor Signaling Respiratory Burst Role Stem cells T-Lymphocyte TLR2 gene TLR4 gene Therapeutic Toll-like receptors cell type combat cytokine dectin 1 fighting immune function improved in vivo killings macrophage member microbial microorganism antigen novel therapeutics precursor cell prevent progenitor public health relevance receptor response stem treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Myelopoiesis replenishes peripheral supplies of myeloid phagocytes in the steady-state, as well as in response to increased demand during infection. Inflammatory mediators produced in response to microbial invasion act on hematopoietic stem and progenitor cells to stimulate myelopoiesis and mobilize myeloid phagocytes to combat infection. Recent data have demonstrated that hematopoietic stem cells, as well as more committed progenitors, express Toll-like receptors (TLRs), and that direct detection of microbial products by these cells can induce myelopoiesis. However, it is currently unclear whether the myeloid cells generated by direct microbial stimulation of progenitors are functionally equivalent to pre-existing myeloid cells. We have observed that hematopoietic progenitors transiently exposed to TLR2 or TLR4 agonists generate macrophages that make less TNF-1 and IL-6 upon TLR stimulation, but more ROS upon Dectin-1 ligation. Our data suggest that myeloid cell function can be altered for an extended period following microbial exposure. This may be an important mechanism for limiting the damaging effects of inflammation, but could also have a previously unappreciated impact on immune function, including the capacity to combat subsequent infections. In this project, we will define the mechanisms underlying this progenitor reprogramming. In Aim 1 we will define the mechanisms by which myeloid precursors are reprogrammed by transient exposure to TLR agonists. We will identify the precursor populations affected, determine whether reprogramming requires direct contact with TLR agonists, define the role of TLR adaptors and other microbial receptors, and determine how long progenitor reprogramming persists. In Aim2 we will determine the mechanisms underlying the altered responsiveness (enhanced oxidative burst but suppressed inflammatory cytokine production) of reprogrammed macrophages. These studies will pave the way for future investigation of the role of progenitor reprogramming in controlling inflammation during primary infection and in establishing susceptibility to subsequent infection, and for the therapeutic exploitation of myeloid progenitor reprogramming for the treatment of inflammatory disease. PUBLIC HEALTH RELEVANCE: Myeloid cells are important for fighting infection, but they also cause inflammation which can result in damage. We are defining how these cells are generated during infection, and how infection affects their function. Clinical manipulation of these cells may improve our ability to fight infection or prevent the damaging effects of inflammation.

描述（由申请人提供）：骨髓生成在稳态下补充外周髓样吞噬细胞的供应，并响应感染期间增加的需求。微生物入侵产生的炎症介质作用于造血干细胞和祖细胞，刺激骨髓生成并动员骨髓吞噬细胞对抗感染。最近的数据表明，造血干细胞以及更多的定型祖细胞表达 Toll 样受体 (TLR)，并且这些细胞直接检测微生物产物可以诱导骨髓细胞生成。然而，目前尚不清楚直接微生物刺激祖细胞产生的骨髓细胞在功能上是否与预先存在的骨髓细胞相同。我们观察到，造血祖细胞短暂暴露于 TLR2 或 TLR4 激动剂，会产生巨噬细胞，在 TLR 刺激下产生较少的 TNF-1 和 IL-6，但在 Dectin-1 连接后产生更多的 ROS。我们的数据表明，在微生物暴露后，骨髓细胞功能可能会在较长时间内发生改变。这可能是限制炎症破坏性影响的重要机制，但也可能对免疫功能（包括抵抗后续感染的能力）产生以前未曾意识到的影响。在这个项目中，我们将定义祖细胞重编程的机制。在目标 1 中，我们将定义通过短暂暴露于 TLR 激动剂来重编程骨髓前体细胞的机制。我们将确定受影响的前体群体，确定重编程是否需要与 TLR 激动剂直接接触，定义 TLR 接头和其他微生物受体的作用，并确定祖细胞重编程持续多长时间。在 Aim2 中，我们将确定重编程巨噬细胞反应性改变（增强氧化爆发但抑制炎症细胞因子产生）的机制。这些研究将为未来研究祖细胞重编程在控制原发感染期间炎症和确定对后续感染的易感性中的作用以及利用骨髓祖细胞重编程治疗炎症性疾病铺平道路。公共卫生相关性：骨髓细胞对于抵抗感染很重要，但它们也会引起炎症，从而导致损害。我们正在定义这些细胞在感染过程中是如何产生的，以及感染如何影响它们的功能。对这些细胞的临床操作可以提高我们抵抗感染的能力或防止炎症的破坏性影响。