Department of Parasitology, Microbiology and Immunology, Biological Sciences Institute, Federal University of Juiz de Fora, Juiz de Fora, MG, Brazil.
Immunology. 2013 Aug;139(4):503-12. doi: 10.1111/imm.12097.
Apoptosis of macrophages has been reported as an effective host strategy to control the growth of intracellular pathogens, including pathogenic mycobacteria. Tumour necrosis factor-α (TNF-α) plays an important role in the modulation of apoptosis of infected macrophages. It exerts its biological activities via two distinct cell surface receptors, TNFR1 and TNFR2, whose extracellular domain can be released by proteolysis forming soluble TNF receptors (sTNFR1 and sTNFR2). The signalling through TNFR1 initiates the majority of the biological functions of TNF-α, leading to either cell death or survival whereas TNFR2 mediates primarily survival signals. Here, the expression of TNF-α receptors and the apoptosis of alveolar macrophages were investigated during the early phase of infection with attenuated and virulent mycobacteria in mice. A significant increase of apoptosis and high expression of TNFR1 were observed in alveolar macrophages at 3 and 7 days after infection with attenuated Mycobacterium bovis but only on day 7 in infection with the virulent M. bovis. Low surface expression of TNFR1 and increased levels of sTNFR1 on day 3 after infection by the virulent strain were associated with reduced rates of apoptotic macrophages. In addition, a significant reduction in apoptosis of alveolar macrophages was observed in TNFR1(-/-) mice at day 3 after bacillus Calmette-Guérin infection. These results suggest a potential role for TNFR1 in mycobacteria-induced alveolar macrophage apoptosis in vivo. In this scenario, shedding of TNFR1 seems to contribute to the modulation of macrophage apoptosis in a strain-dependent manner.
巨噬细胞凋亡已被报道为一种有效的宿主策略，可控制包括致病性分枝杆菌在内的细胞内病原体的生长。肿瘤坏死因子-α（TNF-α）在调节感染巨噬细胞凋亡中起着重要作用。它通过两种不同的细胞表面受体 TNFR1 和 TNFR2 发挥其生物学活性，其细胞外结构域可通过蛋白水解释放形成可溶性 TNF 受体（sTNFR1 和 sTNFR2）。TNFR1 的信号转导启动了 TNF-α 的大多数生物学功能，导致细胞死亡或存活，而 TNFR2 主要介导存活信号。在这里，研究了在小鼠感染减毒和毒力分枝杆菌的早期阶段 TNF-α 受体的表达和肺泡巨噬细胞的凋亡。在感染减毒牛分枝杆菌后 3 天和 7 天，肺泡巨噬细胞中观察到凋亡增加和 TNFR1 高表达，但在感染强毒牛分枝杆菌时仅在第 7 天观察到。在感染强毒株后的第 3 天，TNFR1 的表面表达降低和 sTNFR1 水平升高与凋亡巨噬细胞的减少率相关。此外，在感染卡介苗后第 3 天，TNFR1(-/-) 小鼠的肺泡巨噬细胞凋亡明显减少。这些结果表明 TNFR1 在体内分枝杆菌诱导的肺泡巨噬细胞凋亡中具有潜在作用。在这种情况下，TNFR1 的脱落似乎以菌株依赖的方式有助于调节巨噬细胞凋亡。
