The protein kinase PKR is required for macrophage apoptosis after activation of Toll-like receptor 4

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Abstract
Macrophages are pivotal constituents of the innate immune system, vital for recognition and elimination of microbial pathogens1. Macrophages use Toll-like receptors (TLRs) to detect pathogen-associated molecular patterns—including bacterial cell wall components, such as lipopolysaccharide or lipoteichoic acid, and viral nucleic acids, such as double-stranded (ds)RNA—and in turn activate effector functions, including anti-apoptotic signalling pathways2. Certain pathogens, however, such as Salmonella spp., Shigellae spp. and Yersiniae spp., use specialized virulence factors to overcome these protective responses and induce macrophage apoptosis3. We found that the anthrax bacterium, Bacillus anthracis, selectively induces apoptosis of activated macrophages4 through its lethal toxin, which prevents activation of the anti-apoptotic p38 mitogen-activated protein kinase4. We now demonstrate that macrophage apoptosis by three different bacterial pathogens depends on activation of TLR4. Dissection of anti- and pro-apoptotic signalling events triggered by TLR4 identified the dsRNA responsive protein kinase PKR as a critical mediator of pathogen-induced macrophage apoptosis. The pro-apoptotic actions of PKR are mediated both through inhibition of protein synthesis and activation of interferon response factor 3.