Dynamic changes in Mcl-1 expression regulate macrophage viability or commitment to apoptosis during bacterial clearance
Helen M. Marriott, … , Moira K.B. Whyte, David H. Dockrell
Helen M. Marriott, … , Moira K.B. Whyte, David H. Dockrell
Published February 1, 2005
Citation Information: J Clin Invest. 2005;115(2):359-368. https://doi.org/10.1172/JCI21766.
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Article Infectious disease

Dynamic changes in Mcl-1 expression regulate macrophage viability or commitment to apoptosis during bacterial clearance

Abstract

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-1Exon-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.

Authors

Helen M. Marriott, Colin D. Bingle, Robert C. Read, Karen E. Braley, Guido Kroemer, Paul G. Hellewell, Ruth W. Craig, Moira K.B. Whyte, David H. Dockrell

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Proteasome-mediated degradation of Mcl-1 is associated with pneumococcal...
Proteasome-mediated degradation of Mcl-1 is associated with pneumococcal-associated macrophage apoptosis. (A) Western blot of total protein obtained from MDMs 12 hours and 20 hours after mock infection or infection with pneumococci in the presence or absence of the proteasome inhibitor MG-132, probed with anti–Mcl-1 and anti-actin antibodies. Data are representative of 4 donors in 2 independent experiments. (B) Western blot of the cytosolic fractions from MDMs 20 hours after infection in the presence or absence of MG-132 probed with anti–cytochrome c and anti-actin antibodies. Results are representative of 3 donors from 2 independent experiments. (C) MDMs were incubated in the presence or absence of MG-132, and nuclear features of apoptosis were recorded 20 hours after infection. Results were obtained from 6 donors tested in duplicate. Dunn’s multiple comparison test: MDMs infected with pneumococci without MG-132 vs. with MG-132, P < 0.05. Data are representative of 3 experiments.