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

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.

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Figure 1: Heat-killed B. anthracis (HKBA) and LPS induce macrophage apoptosis through TLR4.
Figure 2: Role of effector molecules in TLR4-induced apoptosis.
Figure 3: PKR is necessary for LPS-induced interferon signalling pathway in macrophages.
Figure 4: PKR is required for LPS-induced macrophage apoptosis.
Figure 5: PKR-deficient macrophages are resistant to pathogen-induced apoptosis.

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Acknowledgements

We thank E. Raz, V. Redecke, S. Akira, J. Inoue, T. Taniguchi and B. Beutler for various knockout mice and bone marrow, J. Bliska for Yersiniae strains, N. Sonenberg and R. Medzhitov for gifts of plasmids and antibodies, and M. Delhase for technical assistance. L.-C.H., J.M.P., J.-L.L. and S.M. were supported by postdoctoral fellowships from the Cancer Research Institute, the Irvington Institute, the International Union Against Cancer and the Japanese Society for Promotion of Science, respectively. Work in the laboratories of M.K., D.G.G. and L.E. was supported by grants from the National Institutes of Health. M.K. is an American Cancer Society Research Professor.

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Correspondence to Michael Karin.

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Hsu, LC., Mo Park, J., Zhang, K. et al. The protein kinase PKR is required for macrophage apoptosis after activation of Toll-like receptor 4. Nature 428, 341–345 (2004). https://doi.org/10.1038/nature02405

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