Pyroptosis maintains the integrity of a granuloma

焦亡维持肉芽肿的完整性

• 批准号: 10887377
• 负责人: Edward A Miao
• 金额: $ 6万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10887377
• 关键词: Abscess; Antigen-Antibody Complex; Bacteria; Bacterial Infections; Biological Models; Biology; C57BL/6 Mouse; CASP1 gene; CASP4 gene; Caspase; Cd68; Cell Death; Cells; Chromobacterium; Chromosome Mapping; Collagen; Complex; DNA; Deposition; Disease; Fibroblasts; Foreign Bodies; Goals; Grant; Granuloma; Granulomatous; Hepatocyte; Homeostasis; Immune; Immune response; Immune system; Immunologic Stimulation; Infection; Infectious Agent; Invaded; Kupffer Cells; Laboratory mice; Lesion; Liver; Macrophage; Modeling; Molecular; Mus; NOS2A gene; Necrosis; Organ; Pathology; Process; Stains; Stimulus; Structure; Susceptibility Gene; T-Lymphocyte; Thick; Tissues; Tuberculosis; Virulence; adaptive immune response; bactericide; cell type; innovation; microbial; mouse model; neutrophil; novel; pathogen; prevent; recruit; response; trait

Granulomas are complex immunologic structures formed in tissues in response to infection. The general function of a granuloma has been elusive because many infections that stimulate granuloma responses do not resolve. Often, granulomas are described as immunologic responses that wall off an infectious agent that cannot be cleared by the immune system. Basic understandings of the fundamentals of a granuloma have been elusive because mouse models where granulomas form are rare or complicated. We have discovered a novel bacterial infection model where the murine immune system forms a granuloma. When mice are infected by Chromobacterium violaceum, the immunologic response fails to clear the bacterium from the liver within the first several days. Then a granuloma forms around the infected lesion, and this complex immunologic response successfully sterilizes the infection and returns the organ to homeostasis typically within 7-14 days post infection. Therefore, we have discovered a novel infectious model where basic granuloma biology can be elucidated. C. violaceum first infects hepatocytes and perhaps Kupffer cells in the liver. This rapidly stimulates a neutrophil swarm within the first day post infection. However, the neutrophil swarm fails to eradicate the infection, and the neutrophils themselves appear to become replicative intracellular niches for the bacterium. Three days post infection the neutrophil swarm dies and forms a central necrotic core of the lesion. Macrophages begin to appear at the periphery of the lesion at 3 days post infection and form a thick macrophage zone that surrounds the necrotic core by day 5-7. Thereafter, the bacteria are killed through the action of inducible nitric oxide synthase, the granuloma is sterilized, and shrinks over the next week. Granuloma burdens are sterilized between 7-21 days post infection. This all occurs in the absence of T cells or other adaptive immune cells. In this grant, we use this novel granuloma model to explore the importance of pyroptotic cell death in the granuloma.

肉芽肿是组织中响应感染而形成的复杂免疫结构。肉芽肿的一般功能一直难以捉摸，因为许多刺激肉芽肿反应的感染无法治愈。通常，肉芽肿被描述为免疫反应，它隔离了免疫系统无法清除的感染因子。对肉芽肿基本原理的基本了解一直难以捉摸，因为形成肉芽肿的小鼠模型很少见或很复杂。我们发现了一种新的细菌感染模型，其中小鼠免疫系统形成肉芽肿。当小鼠被紫色色杆菌感染时，免疫反应无法在最初几天内清除肝脏中的细菌。然后，感染病灶周围会形成肉芽肿，这种复杂的免疫反应通常会在感染后 7-14 天内成功消除感染并使器官恢复稳态。因此，我们发现了一种新的感染模型，可以阐明基本的肉芽肿生物学。紫色棒状杆菌首先感染肝细胞，或许还感染肝脏中的库普弗细胞。这会在感染后的第一天迅速刺激中性粒细胞群。然而，中性粒细胞群未能根除感染，并且中性粒细胞本身似乎成为细菌的复制性细胞内生态位。感染后三天，中性粒细胞群死亡并形成病变的中央坏死核心。感染后 3 天，巨噬细胞开始出现在病变周围，并在第 5-7 天形成围绕坏死核心的厚巨噬细胞区。此后，细菌通过诱导型一氧化氮合酶的作用被杀死，肉芽肿被灭菌，并在接下来的一周内缩小。肉芽肿负担在感染后 7-21 天内进行消毒。这一切都发生在没有 T 细胞或其他适应性免疫细胞的情况下。在这笔资助中，我们使用这种新型肉芽肿模型来探索肉芽肿中焦亡细胞死亡的重要性。