Dynamic changes in Mcl-1 expression regulate macrophage viability or commitment to apoptosis during bacterial clearance
Dynamic changes in Mcl-1 expression regulate macrophage viability or commitment to apoptosis during bacterial clearance
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DOI：
10.1172/jci200521766
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发表时间：
2005-02-01
影响因子：
15.9
通讯作者：
Dockrell, DH
中科院分区：
文献类型：
--
作者：
Marriott, HM;Bingle, CD;Dockrell, DH
巨噬细胞是细菌清除的关键效应物，尽管暴露于有毒细菌产物，但必须保持活力，直到执行关键的抗菌功能。随后，宿主介导的巨噬细胞凋亡有助于感染的解决。巨噬细胞从对细胞凋亡的抗性转变为对细胞凋亡的易感性的能力对于有效的宿主先天免疫应答是重要的。我们使用肺炎球菌相关巨噬细胞凋亡模型，研究了Mcl-1（巨噬细胞寿命的重要调节因子）在从生存能力到凋亡的转变中的作用。在暴露于肺炎球菌后，巨噬细胞最初上调Mcl-1蛋白并维持活力长达14小时。随后，巨噬细胞减少全长Mcl-1的表达并上调Mcl-1的34-kDa同种型，其对应于新的仅BH3剪接变体Mcl-1（外显子-1）。Mcl-1蛋白表达的变化与线粒体膜透化相关，其特征在于线粒体内跨膜电位的丧失以及细胞色素c和凋亡诱导因子的易位。肺炎球菌感染后，表达全长人Mcl-1作为转基因的巨噬细胞表现出细胞凋亡和细菌杀伤的延迟。mcl-1转基因小鼠清除肺部肺炎球菌的效率低于非转基因小鼠。Mcl-1表达的动态变化决定巨噬细胞的活力以及抗菌宿主防御。
Macrophages are critical effectors of bacterial clearance and must retain viability, despite exposure to toxic bacterial products, until key antimicrobial functions are performed. Subsequently, host-mediated macrophage apoptosis aids resolution of infection. The ability of macrophages to make this transition from resistance to susceptibility to apoptosis is important for effective host innate immune responses. We investigated the role of Mcl-1, an essential regulator of macrophage lifespan, in this switch from viability to apoptosis, using the model of pneumococcal-associated macrophage apoptosis. Upon exposure to pneumococci, macrophages initially upregulate Mcl-1 protein and maintain viability for up to 14 hours. Subsequently, macrophages reduce expression of full-length Mcl-1 and upregulate a 34-kDa isoform of Mcl-1 corresponding to a novel BH3-only splice variant, Mcl-1(Exon-1) Change in expression of Mcl-1 protein is associated with mitochondrial membrane permeabilization, which is characterized by loss of mitochondrial inner transmembrane potential and translocation of cytochrome c and apoptosis-inducing factor. Following pneumococcal infection, macrophages expressing full-length human Mcl-1 as a transgene exhibit a delay in apoptosis and in bacterial killing. Mcl-1 transgenic mice clear pneumococci from the lung less efficiently than nontransgenic mice. Dynamic changes in Mcl-1 expression determine macrophage viability as well as antibacterial host defense.