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


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.


  1. Aderem, A. & Ulevitch, R. J. Toll-like receptors in the induction of the innate immune response. Nature 406, 782–787 (2000)

    Article  CAS  PubMed  Google Scholar 

  2. Medzhitov, R. Toll-like receptors and innate immunity. Nature Rev. Immunol. 1, 135–145 (2001)

    Article  CAS  Google Scholar 

  3. Weinrauch, Y. & Zychlinsky, A. The induction of apoptosis by bacterial pathogens. Annu. Rev. Microbiol. 53, 155–187 (1999)

    Article  CAS  PubMed  Google Scholar 

  4. Park, J. M., Greten, F. R., Li, Z. W. & Karin, M. Macrophage apoptosis by anthrax lethal factor through p38 MAP kinase inhibition. Science 297, 2048–2051 (2002)

    Article  ADS  CAS  PubMed  Google Scholar 

  5. Poltorak, A. et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282, 2085–2088 (1998)

    Article  ADS  CAS  PubMed  Google Scholar 

  6. Medzhitov, R., Preston-Hurlburt, P. & Janeway, C. A. Jr A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 388, 394–397 (1997)

    ADS  CAS  PubMed  Google Scholar 

  7. Hoebe, K. et al. Identification of Lps2 as a key transducer of MyD88-independent TIR signalling. Nature 424, 743–748 (2003)

    Article  ADS  CAS  PubMed  Google Scholar 

  8. Yamamoto, M. et al. TRAM is specifically involved in the Toll-like receptor 4-mediated MyD88-independent signaling pathway. Nature Immunol. 4, 1144–1150 (2003)

    Article  CAS  Google Scholar 

  9. Kawai, T., Adachi, O., Ogawa, T., Takeda, K. & Akira, S. Unresponsiveness of MyD88-deficient mice to endotoxin. Immunity 11, 115–122 (1999)

    Article  CAS  PubMed  Google Scholar 

  10. Naito, A. et al. Severe osteopetrosis, defective interleukin-1 signalling and lymph node organogenesis in TRAF6-deficient mice. Genes Cells 4, 353–362 (1999)

    Article  CAS  PubMed  Google Scholar 

  11. Karin, M. & Lin, A. NF-κB at the crossroads of life and death. Nature Immunol. 3, 221–227 (2002)

    Article  CAS  Google Scholar 

  12. Li, Z. W., Omori, S. A., Labuda, T., Karin, M. & Rickert, R. C. Ikkβ is required for peripheral B cell survival and proliferation. J. Immunol. 170, 4630–4637 (2003)

    Article  CAS  PubMed  Google Scholar 

  13. Kuhn, R., Schwenk, F., Aguet, M. & Rajewsky, K. Inducible gene targeting in mice. Science 269, 1427–1429 (1995)

    ADS  CAS  PubMed  Google Scholar 

  14. Horng, T., Barton, G. M. & Medzhitov, R. TIRAP: an adapter molecule in the Toll signaling pathway. Nature Immunol. 2, 835–841 (2001)

    Article  CAS  Google Scholar 

  15. Kaufman, R. J. Double-stranded RNA-activated protein kinase mediated virus-induced apoptosis: a new role for an old actor. Proc. Natl Acad. Sci. USA 96, 116935 (1999)

    Google Scholar 

  16. Chu, W. M. et al. JNK2 and IKKβ are required for activating the innate response to viral infection. Immunity 11, 721–731 (1999)

    Article  CAS  PubMed  Google Scholar 

  17. Samuel, C. E. Antiviral actions of interferons. Clin. Microbiol. Rev. 14, 778–809 (2001)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Lehner, M., Felzmann, T., Clodi, K. & Holter, W. Type I interferons in combination with bacterial stimuli induce apoptosis of monocyte-derived dendritic cells. Blood 98, 736–742 (2001)

    Article  CAS  PubMed  Google Scholar 

  19. Muller, U. et al. Functional role of type I and type II interferons in antiviral defense. Science 264, 1918–1921 (1994)

    Article  ADS  CAS  PubMed  Google Scholar 

  20. Saelens, X., Kalai, M. & Vandenabeele, P. Translation inhibition in apoptosis: caspase-dependent PKR activation and eIF2-alpha phosphorylation. J. Biol. Chem. 276, 41620–41628 (2001)

    Article  CAS  PubMed  Google Scholar 

  21. Diebold, S. S. et al. Viral infection switches non-plasmacytoid dendritic cells into high interferon producers. Nature 424, 324–328 (2003)

    Article  ADS  CAS  PubMed  Google Scholar 

  22. Scheuner, D. et al. Translational control is required for the unfolded protein response and in vivo glucose homeostasis. Mol. Cell 7, 1165–1176 (2001)

    Article  CAS  PubMed  Google Scholar 

  23. Heylbroeck, C. et al. The IRF-3 transcription factor mediates Sendai virus-induced apoptosis. J. Virol. 74, 3781–3792 (2000)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Sato, M. et al. Distinct and essential roles of transcription factors IRF-3 and IRF-7 in response to viruses for IFN-α/β gene induction. Immunity 13, 539–548 (2000)

    Article  CAS  PubMed  Google Scholar 

  25. Orth, K. et al. Disruption of signaling by Yersinia effector YopJ, a ubiquitin-like protein protease. Science 290, 1594–1597 (2000)

    Article  ADS  CAS  PubMed  Google Scholar 

  26. Rosenberger, C. M. & Finlay, B. B. Phagocyte sabotage: disruption of macrophage signalling by bacterial pathogens. Nature Rev. Mol. Cell Biol. 4, 385–396 (2003)

    Article  CAS  Google Scholar 

  27. Durbin, R. K., Mertz, S. E., Koromilas, A. E. & Durbin, J. E. PKR protection against intranasal vesicular stomatitis virus infection is mouse strain dependent. Viral Immunol. 15, 41–51 (2002)

    Article  CAS  PubMed  Google Scholar 

  28. Yang, Y. L. et al. Deficient signaling in mice devoid of double-stranded RNA-dependent protein kinase. EMBO J. 14, 6095–6106 (1995)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Browne, S. H., Lesnick, M. L. & Guiney, D. G. Genetic requirements for salmonella-induced cytopathology in human monocyte-derived macrophages. Infect. Immun. 70, 7126–7135 (2002)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Zhang, Y. & Bliska, J. B. Role of Toll-like receptor signaling in the apoptotic response of macrophages to Yersinia infection. Infect. Immun. 71, 1513–1519 (2003)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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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).

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