Alternatively activated macrophages during helminth infection

蠕虫感染期间巨噬细胞的选择性激活

• 批准号: 9976440
• 负责人: Victor J. Torres
• 金额: $ 48.16万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9976440
• 关键词: ATAC-seq; Acute; Adipose tissue; Adopted; Affect; Atherosclerosis; Biology; CD4 Positive T Lymphocytes; Cell Count; Cell Lineage; Cells; Chromatin; Chromatin Structure; Coupling; Data; Developing Countries; Embryonic Development; Failure; Gene Expression; Goals; Granuloma; Helminths; Hepatic Granuloma; Immune response; Immunity; Infection; Inflammation; Inflammatory; Inflammatory Response; Interleukin-4; Intestines; Liver; Macrophage Activation; Maps; Mediating; Modeling; Morbidity - disease rate; Mus; Parasites; Pathology; Pathway interactions; Phenotype; Physiological Processes; Play; Population; Process; Property; Regulator Genes; Regulatory Element; Resolution; Role; Scanning; Schistosoma mansoni; Schistosomiasis; Signal Transduction; Site; Supplementation; Testing; Tissues; Transcription Factor AP-1; Translating; Tretinoin; Vitamin A; Vitamin A Deficiency; cell type; chronic inflammatory disease; combat; egg; experimental study; genome-wide; helminth infection; inhibitor/antagonist; macrophage; micronutrient deficiency; monocyte; mortality; novel; prevent; progenitor; residence; response; retinoic acid receptor alpha; transcription factor; tumor microenvironment; wound healing

Abstract Schistosomiasis affects more than 200 million people worldwide. During infection, the type 2 immune response and M2 macrophages play a critical role in granuloma formation around the eggs and enable the host to tolerate the tissue damage caused by these eggs, which become embedded in the liver. We previously identified phenotypic and functional differences between M2 macrophages derived from either tissue resident macrophages or inflammatory monocytes. We also determined that the M2 macrophages in acute liver granulomas formed after infection with Schistosoma mansoni are derived from inflammatory Ly6Chigh monocytes. However, as the granulomas mature and become more organized, the inflammatory macrophages in the granuloma eventually adopt features of tissue resident M2 macrophages. This phenotypic conversion into tissue resident M2 macrophages is disrupted in mice with vitamin A deficiency, an important micronutrient deficiency in developing countries, which leads to increased morbidity during infection. The key metabolite of vitamin A, retinoic acid (RA), may therefore be essential for the normal function of macrophages in the liver. We hypothesize that RA signaling enables inflammatory macrophages around the S. mansoni egg granulomas to adopt the properties of tissue resident macrophages in the local microenvironment. In contrast to S. mansoni, other helminths (e.g. Heligmosoides polygyrus) can induce expansion of M2 macrophages from tissue-resident macrophage populations. Hence, different helminth infections induce M2 activation in macrophages of different lineages. Differences in open chromatin regions may regulate differential activation of M2 macrophages from different cellular lineages. We have investigated open regions of chromatin in the different M2 macrophages. By coupling genome-wide gene expression data with sequencing data on chromatin structure, we are uncovering the regulatory networks and identifying key transcription factors that control the differential responses to IL-4 for different lineage of M2 macrophages. We hypothesize that chromatin structure is reorganized when inflammatory macrophages around S. mansoni egg granulomas adopt properties of tissue resident M2 macrophages. Failure of this process may increase mortality during infection. In this proposal we will (Aim 1) determine the role and mechanism of action of retinoic acid (RA) in regulating conversion to a tissue resident M2 macrophages phenotype and (Aim 2) identify gene regulatory networks mediating differential M2 activation of monocyte derived M2 macrophages and tissue resident M2 macrophages, and the phenotypic conversion from inflammatory macrophages to a tissue resident phenotype. While our focus is to characterize the biology of M2 macrophages during helminth infections, our findings should be translatable to the many other sites and physiological processes whereby M2 macrophages play an important functional role (e.g. in adipose tissues, atherosclerosis, tumor microenvironments and during wound repair). Hence, the impact of these studies should be broader than just helminth infections alone.

血吸虫病影响着全世界2亿多人。在感染过程中，2型 免疫应答和M2巨噬细胞在卵周围肉芽肿形成中起关键作用， 使宿主能够忍受这些卵造成的组织损伤，这些卵嵌入肝脏。 我们先前鉴定了来源于大肠杆菌的M2巨噬细胞之间的表型和功能差异。 或者组织驻留巨噬细胞或者炎性单核细胞。我们还确定M2巨噬细胞 在曼氏血吸虫感染后形成的急性肝肉芽肿中， Ly 6Chigh单核细胞。然而，随着肉芽肿的成熟和组织化， 肉芽肿中的巨噬细胞最终采用组织驻留的M2巨噬细胞的特征。这种表型 在维生素A缺乏的小鼠中，M2巨噬细胞向组织驻留的转化被破坏，这是一个重要的 在发展中国家，微量营养素缺乏导致感染期间发病率增加。关键 因此，维生素A的代谢产物视黄酸（RA）可能对巨噬细胞的正常功能至关重要 在肝脏里。我们假设RA信号使S.曼氏卵 肉芽肿在局部微环境中采用组织驻留巨噬细胞的特性。 与S. mansoni，其他蠕虫（如Heligmosoides polygyrus）可诱导M2扩增 巨噬细胞来自组织驻留的巨噬细胞群体。因此，不同的蠕虫感染诱导M2 在不同谱系的巨噬细胞中活化。开放染色质区域的差异可以调节分化 来自不同细胞谱系的M2巨噬细胞的活化。我们研究了染色质的开放区域 在不同的M2巨噬细胞中。通过将全基因组基因表达数据与测序数据相结合， 染色质结构，我们正在揭示调控网络，并确定关键的转录因子， 控制不同谱系M2巨噬细胞对IL-4的不同反应。我们假设 当S.曼氏虫卵肉芽肿 组织驻留M2巨噬细胞的性质。这一过程的失败可能会增加感染期间的死亡率。 在这项建议中，我们将（目的1）确定维甲酸（RA）在以下方面的作用和作用机制： 调节向组织驻留M2巨噬细胞表型的转化，并且（目的2）鉴定基因调节 介导单核细胞衍生的M2巨噬细胞和组织驻留M2的差异M2活化的网络 巨噬细胞，以及从炎性巨噬细胞到组织驻留表型的表型转化。 虽然我们的重点是描述蠕虫感染期间M2巨噬细胞的生物学特征，但我们的研究结果 应该可以翻译到许多其他网站和生理过程，其中M2巨噬细胞发挥作用， 重要的功能作用（例如在脂肪组织、动脉粥样硬化、肿瘤微环境和创伤期间 修复）。因此，这些研究的影响应该比仅仅蠕虫感染更广泛。