Pyroptosis maintains the integrity of a granuloma

肉芽肿是一种复杂的免疫结构，在组织中形成对感染的反应。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并未痊愈。通常，肉芽肿被描述为免疫反应，将无法被免疫系统清除的感染源隔开。肉芽肿的基本原理一直难以理解，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，在这种模型中，小鼠的免疫系统会形成肉芽肿。当小鼠感染紫色铬杆菌时，免疫反应在最初的几天内无法将细菌从肝脏中清除出去。然后在感染的病变周围形成肉芽肿，这种复杂的免疫反应成功地消毒了感染，并在感染后7-14天内使器官恢复到动态平衡。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。紫球藻首先感染肝细胞，也可能感染肝脏中的库普弗细胞。这会在感染后的第一天内迅速刺激中性粒细胞群。然而，中性粒细胞群未能根除感染，中性粒细胞本身似乎成为细菌复制的细胞内利基。感染三天后，中性粒细胞群死亡，并形成病变的中心坏死核。巨噬细胞在感染后3天开始出现在病变的边缘，并在第5-7天形成一个围绕坏死核心的厚厚的巨噬细胞带。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。这一切都是在缺乏T细胞或其他适应性免疫细胞的情况下发生的。在这项资助中，我们使用这种新的肉芽肿模型来探索嗜酸性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.