Frankenberg Tobias, Kirschnek Susanne, Häcker Hans, Häcker Georg
Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München, Munich, Germany.
Eur J Immunol. 2008 Jan;38(1):204-15. doi: 10.1002/eji.200737379.
Phagocytosis and intracellular destruction of pathogens by phagocytes is a crucial defense mechanism of the innate immune response during infection. It has been reported a number of times that the interaction with pyogenic, extracellular bacteria leads to the apoptotic death of phagocytes. The signaling events that cause this form of cell death are largely unknown. In this study, we demonstrate a link between uptake, killing and degradation of Escherichia coli bacteria and induction of apoptosis in macrophages. Treatment of murine RAW 264.7 macrophages with bafilomycin A(1), a phagosome acidification inhibitor, reduced killing and degradation of phagocytosed bacteria and significantly decreased macrophage apoptosis. The stable overexpression of constitutively active or dominant-negative mutants of the small GTPase Rab5a increased bacterial phagocytosis and consecutively apoptosis. In these cells, relative killing and degradation were not affected, linking the increased apoptosis to enhanced uptake and suggesting that the apoptosis-inducing signal derives from the higher incidence of degradation events or an accumulation of phagosomes of a late maturation stage. These results thus provide a link between bacterial phagocytosis and degradation and the induction of apoptosis in macrophages. We propose that this form of apoptosis is the physiological conclusion of an innate immune response against pyogenic bacteria.
吞噬细胞对病原体的吞噬作用及细胞内破坏是感染期间固有免疫反应的关键防御机制。多次报道称，与化脓性细胞外细菌的相互作用会导致吞噬细胞凋亡死亡。导致这种细胞死亡形式的信号事件在很大程度上尚不清楚。在本研究中，我们证明了大肠杆菌的摄取、杀伤和降解与巨噬细胞凋亡诱导之间的联系。用吞噬体酸化抑制剂巴弗洛霉素A(1)处理小鼠RAW 264.7巨噬细胞，可降低吞噬细菌的杀伤和降解，并显著减少巨噬细胞凋亡。小GTP酶Rab5a的组成型活性或显性负性突变体的稳定过表达增加了细菌吞噬作用，并随之增加了细胞凋亡。在这些细胞中，相对杀伤和降解不受影响，将增加的细胞凋亡与增强的摄取联系起来，表明凋亡诱导信号源自降解事件的更高发生率或晚期成熟阶段吞噬体的积累。因此，这些结果提供了细菌吞噬和降解与巨噬细胞凋亡诱导之间的联系。我们提出，这种凋亡形式是针对化脓性细菌的固有免疫反应的生理结局。
