Division of Rheumatology, Immunology, and Allergy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Mucosal Immunol. 2011 May;4(3):279-87. doi: 10.1038/mi.2011.3. Epub 2011 Feb 9.
Two different forms of death are commonly observed when Mycobacterium tuberculosis (Mtb)-infected macrophages die: (i) necrosis, a death modality defined by cell lysis and (ii) apoptosis, a form of death that maintains an intact plasma membrane. Necrosis is a mechanism used by bacteria to exit the macrophage, evade host defenses, and spread. In contrast, apoptosis of infected macrophages is associated with diminished pathogen viability. Apoptosis occurs when tumor necrosis factor activates the extrinsic death domain pathway, leading to caspase-8 activation. In addition, mitochondrial outer membrane permeabilization leading to activation of the intrinsic apoptotic pathway is required. Both pathways lead to caspase-3 activation, which results in apoptosis. We have recently demonstrated that during mycobacterial infection, cell death is regulated by the eicosanoids, prostaglandin E(2) (proapoptotic) and lipoxin (LX)A(4) (pronecrotic). Although PGE(2) protects against necrosis, virulent Mtb induces LXA(4) and inhibits PGE(2) production. Under such conditions, mitochondrial inner membrane damage leads to macrophage necrosis. Thus, virulent Mtb subverts eicosanoid regulation of cell death to foil innate defense mechanisms of the macrophage.
当结核分枝杆菌(Mtb)感染的巨噬细胞死亡时,通常会观察到两种不同形式的死亡:(i)坏死,这是一种定义为细胞裂解的死亡方式,以及(ii)凋亡,这是一种保持完整质膜的死亡形式。坏死是细菌逃离巨噬细胞、逃避宿主防御和传播的一种机制。相比之下,感染的巨噬细胞凋亡与病原体活力降低有关。当肿瘤坏死因子激活外在死亡域途径时,会导致半胱天冬酶-8 的激活,从而发生细胞凋亡。此外,需要线粒体外膜通透性增加以激活内在凋亡途径。这两种途径都会导致半胱天冬酶-3 的激活,从而导致凋亡。我们最近证明,在分枝杆菌感染期间,细胞死亡受到类二十烷酸的调节,即前列腺素 E2(促凋亡)和脂氧素 A4(促坏死)。虽然 PGE2 可以预防坏死,但毒力结核分枝杆菌会诱导 LXA4 的产生并抑制 PGE2 的产生。在这种情况下,线粒体内膜损伤会导致巨噬细胞坏死。因此,毒力结核分枝杆菌颠覆了类二十烷酸对细胞死亡的调节,以挫败巨噬细胞的先天防御机制。