Pyroptosis maintains the integrity of a granuloma

肉芽肿是组织对感染反应形成的复杂免疫结构。肉芽肿的一般功能一直难以捉摸，因为许多感染刺激肉芽肿反应不解决。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。由于肉芽肿形成的小鼠模型罕见或复杂，对肉芽肿基本原理的基本理解一直难以捉摸。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。当小鼠被紫色细菌感染时，免疫反应不能在最初几天内清除肝脏中的细菌。然后在受感染的病变周围形成肉芽肿，这种复杂的免疫反应成功地对感染进行了消毒，通常在感染后7-14天内使器官恢复稳态。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。紫梭菌首先感染肝细胞，可能感染肝脏中的库普弗细胞。这在感染后的第一天内迅速刺激中性粒细胞群。然而，中性粒细胞群不能根除感染，中性粒细胞本身似乎成为细菌复制的细胞内壁龛。感染三天后，中性粒细胞群死亡，形成病灶的中心坏死核心。在感染后3天，巨噬细胞开始出现在病变周围，并在第5-7天形成厚的巨噬细胞区包围坏死核心。之后，细菌通过诱导型一氧化氮合酶的作用被杀死，肉芽肿被消毒，并在接下来的一周内缩小。肉芽肿负担在感染后7-21天内消毒。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。在本研究中，我们使用这种新型肉芽肿模型来探讨热噬细胞死亡在肉芽肿中的重要性。

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.