Chowdhury Chanchal Sur, Kinsella Rachel L, McNehlan Michael E, Naik Sumanta K, Lane Daniel S, Talukdar Priyanka, Smirnov Asya, Dubey Neha, Rankin Ananda N, McKee Samuel R, Woodson Reilly, Hii Abigail, Chavez Sthefany M, Kreamalmeyer Darren, Beatty Wandy, Mattila Joshua T, Stallings Christina L
Department of Molecular Microbiology, Center for Women's Infectious Disease Research, Washington University School of Medicine, St. Louis, MO 63110, USA.
Department of Infectious Diseases and Microbiology, University of Pittsburgh School of Public Health, Pittsburgh, PA 15261, USA.
Cell Host Microbe. 2024 Dec 11;32(12):2092-2111.e7. doi: 10.1016/j.chom.2024.11.008. Epub 2024 Dec 4.
Neutrophils are the most abundant cell type in the airways of tuberculosis patients. Mycobacterium tuberculosis (Mtb) infection induces the release of neutrophil extracellular traps (NETs); however, the molecular regulation and impact of NET release on Mtb pathogenesis are unknown. We find that during Mtb infection in neutrophils, PAD4 citrullinates histones to decondense chromatin that gets released as NETs in a manner that can maintain neutrophil viability and promote Mtb replication. Type I interferon promotes the formation of chromatin-containing vesicles that allow NET release without compromising plasma membrane integrity. Analysis of nonhuman primate granulomas supports a model where neutrophils are exposed to type I interferon from macrophages as they migrate into the granuloma, thereby enabling the release of NETs associated with necrosis and caseation. Our data reveal NET release as a promising target to inhibit Mtb pathogenesis.
中性粒细胞是肺结核患者气道中最丰富的细胞类型。结核分枝杆菌（Mtb）感染会诱导中性粒细胞胞外诱捕网（NETs）的释放；然而，NET释放的分子调控及其对Mtb发病机制的影响尚不清楚。我们发现，在中性粒细胞受到Mtb感染期间，肽精氨酸脱亚氨酶4（PAD4）使组蛋白瓜氨酸化，从而使染色质解聚，以一种能够维持中性粒细胞活力并促进Mtb复制的方式作为NETs释放出来。I型干扰素促进含染色质囊泡的形成，使NETs得以释放而不损害质膜完整性。对非人类灵长类动物肉芽肿的分析支持了一种模型，即中性粒细胞在迁移到肉芽肿中时会接触到来自巨噬细胞的I型干扰素，从而使得与坏死和干酪样变相关的NETs得以释放。我们的数据表明，NET释放是抑制Mtb发病机制的一个有前景的靶点。
