Protective and pathologic functions of macrophages induced by helminths

蠕虫诱导的巨噬细胞的保护和病理功能

• 批准号: 10062803
• 负责人: William Clark Gause
• 金额: $ 50.79万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-20 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10062803
• 关键词: Acute; Address; Adoptive Transfer; Alveolar Macrophages; Antigen-Presenting Cells; Automobile Driving; Basophils; Biological Assay; Cells; Characteristics; Child; Communities; Complex; Data; Development; Economic Burden; Environment; Equilibrium; Event; Exhibits; Fetal Development; Growth; Helminths; Human; Immune; Immune response; Immune system; Immunity; In Vitro; Individual; Infection; Inflammation; Instruction; Intestines; Laboratories; Larva; Lead; Literature; Lung; Macrophage Activation; Malnutrition; Mammals; Mediating; Methodology; Molecular; Mus; Nippostrongylus; Parasites; Pathologic; Pathology; Pathway interactions; Patients; Phenotype; Play; Population; Prevalence; Production; Publishing; Reporting; Resistance; Resources; Risk; Role; Skin; Soil; Structure of parenchyma of lung; System; Testing; Tissues; Work; base; combat; cytokine; experimental study; granulocyte; health economics; helminth infection; immunopathology; insight; macrophage; monocyte; neutrophil; novel; programs; pulmonary function; response; wound healing

ABSTRACT The global prevalence of soil transmitted helminth infections is estimated at two billion individuals infected, with an estimated 870 million children at risk of becoming infected. Helminth infections can lead to significant malnutrition, growth retardation, severe immunopathology, and exert enormous economic burdens on local communities. Helminth parasites take complex migratory cycles through multiple tissues before entering the intestine of their host. To combat these challenges, the mammalian immune system has evolved mechanisms to maintain a delicate balance between promoting beneficial inflammation needed to reduce parasitic burdens and limiting pathologic inflammation to maintain tissue integrity. The importance of maintaining this balance is evident by the severe pathology that presents in patients exhibiting dysregulated immune responses to helminths. Despite the importance of balancing protective and pathologic responses in the context of helminth infections, the cellular and molecular events that regulate these pathways remain unknown. It is well established that T helper type 2 (TH2) cytokine responses, characteristics of helminth-induced immunity in humans and mice, are required to both promote worm clearance and limit infection-induced tissue damage. An emerging body of literature has now shown that type 2 cytokine-activated macrophages operate as critical regulators of these distinct pathways. In addition, our recent work has also demonstrated that interactions between neutrophils and lung macrophages are required for macrophages to acquire anti-Nippostrongylus brasiliensis (Nb) effector functions in the airways. Moreover, our preliminary data suggest that interactions with basophil populations are required for macrophages to initiate wound healing responses in the lung. Collectively these studies provide the hypothesis that coordinated interactions with Nb-primed innate immune cell populations are necessary for macrophages to acquire host-protective effector functions. This will be directly tested in Aim 1 of this proposal focused on interrogating the accessory cells necessary to promote macrophage activation in the lung following Nb infection. It is well established that long-lived tissue-derived macrophages (TD-Macs) populate the lungs during fetal development, while monocyte-derived macrophages (Mo-Macs) accumulate in tissue environments in the context of ongoing inflammation. Further, it has been demonstrated that TD-Macs and Mo-Macs can exhibit distinct phenotypes in the context of helminth infections. Despite these advances the distinct contributions of TD-Macs and Mo-Macs to anti-helminth immunity and tissue integrity remain unknown. This will be directly tested in Aim 2 of this proposal focused on elucidating the distinct and common effector functions of lung macrophage populations following Nb infection. These aims will be addressed employing the collective intellectual and scientific resources of the Siracusa and Gause laboratories and the results of these studies will increase our understanding of how pulmonary macrophages are programed in the context of acute inflammation.

抽象的 全球土壤传播蠕虫感染流行率估计有 20 亿人感染，其中 估计有 8.7 亿儿童面临感染风险。蠕虫感染可导致严重的 营养不良、生长迟缓、严重的免疫病理，给当地带来巨大的经济负担 社区。蠕虫寄生虫在进入人体之前会经历多个组织的复杂迁徙周期 他们的宿主的肠道。为了应对这些挑战，哺乳动物的免疫系统已经进化出机制 在促进有益炎症和减少寄生虫负担之间保持微妙的平衡 限制病理性炎症以维持组织完整性。维持这种平衡的重要性在于 表现出免疫反应失调的患者中出现的严重病理学是显而易见的 蠕虫。尽管平衡保护性反应和病理性反应很重要 在蠕虫感染中，调节这些途径的细胞和分子事件仍然未知。它 众所周知，2 型辅助性 T (TH2) 细胞因子反应是蠕虫诱导免疫的特征 在人类和小鼠中，需要促进蠕虫清除并限制感染引起的组织损伤。 大量新兴文献现已表明，2 型细胞因子激活的巨噬细胞发挥着至关重要的作用。 这些不同途径的调节者。此外，我们最近的工作还表明，相互作用 中性粒细胞和肺巨噬细胞之间的相互作用是巨噬细胞获得抗日圆线虫所需的 巴西 (Nb) 效应器在气道中发挥作用。此外，我们的初步数据表明，与 巨噬细胞需要嗜碱性粒细胞群来启动肺部伤口愈合反应。集体 这些研究提供了与铌引发的先天免疫细胞协调相互作用的假设 群体是巨噬细胞获得宿主保护效应功能所必需的。这将直接 该提案的目标 1 中进行了测试，重点是询问促进促进所需的辅助细胞 Nb 感染后肺部巨噬细胞激活。众所周知，长寿命的组织来源 巨噬细胞（TD-Mac）在胎儿发育过程中填充在肺部，而单核细胞衍生的巨噬细胞 （Mo-Mac）在持续炎症的情况下在组织环境中积累。此外，已经 证明 TD-Mac 和 Mo-Mac 在蠕虫感染的情况下可以表现出不同的表型。 尽管取得了这些进展，但 TD-Mac 和 Mo-Mac 对抗蠕虫免疫和抗蠕虫免疫的独特贡献 组织完整性仍未知。这将在本提案的目标 2 中直接进行测试，重点是阐明 Nb 感染后肺巨噬细胞群的独特和共同效应功能。这些目标将 利用锡拉库扎和高斯的集体智力和科学资源来解决这个问题 实验室和这些研究的结果将增加我们对肺巨噬细胞如何 是在急性炎症的背景下编程的。