Alternatively activated macrophages during helminth infection

摘要血吸虫病影响着全球2亿多人。在感染期间，2型 免疫反应和M2巨噬细胞在卵周围肉芽肿的形成中起关键作用 使宿主能够容忍这些虫卵对组织造成的损害，这些虫卵嵌入肝脏。 我们之前已经鉴定了来自于 要么是组织内停留的巨噬细胞，要么是炎性单核细胞。我们还测定了M2巨噬细胞 在急性肝脏中，感染曼氏血吸虫后形成的肉芽肿源于炎症 Ly6鸡单核细胞。然而，随着肉芽肿成熟并变得更有组织化，炎性 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 维生素A缺乏的小鼠向组织驻留的M2巨噬细胞的转化被破坏，这是一个重要的 发展中国家的微量营养素缺乏，导致感染期间发病率增加。钥匙 因此，维生素A的代谢物维甲酸(RA)对巨噬细胞的正常功能可能是必不可少的 在肝脏里。我们假设RA信号使曼氏血吸虫虫卵周围的炎性巨噬细胞 肉芽肿采用局部微环境中组织驻留巨噬细胞的特性。 与曼氏丝虫不同，其他蠕虫(如多回螺旋线虫)可引起M2的扩张 来自组织驻留的巨噬细胞群的巨噬细胞。因此，不同的蠕虫感染可诱发M2 不同谱系的巨噬细胞的激活。开放染色质区域的差异可能调节差异 来自不同细胞系的M2巨噬细胞的激活。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，我们正在发现调控网络并识别关键的转录因子 控制不同系M2巨噬细胞对IL-4的差异反应。我们假设 曼氏血吸虫卵肉芽肿周围炎性巨噬细胞采用染色质结构重组 组织驻留的M2巨噬细胞的特性。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(目标1)确定维甲酸(RA)在 调节转化为组织驻留的M2巨噬细胞表型和(目标2)识别基因调节 单核细胞来源的M2巨噬细胞和组织驻留M2的不同M2激活网络 巨噬细胞，以及从炎性巨噬细胞到组织驻留表型的表型转换。 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，但我们的发现 应该可以翻译到许多其他部位和生理过程中，M2巨噬细胞发挥着 重要的功能作用(例如，在脂肪组织、动脉粥样硬化、肿瘤微环境和伤口过程中 修复)。因此，这些研究的影响应该更广泛，而不仅仅是蠕虫感染。

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.