Editors' ChoiceImmunology

For Whom the Toll Receptor Signals Death

Science's STKE  23 Mar 2004:
Vol. 2004, Issue 225, pp. tw103-TW103
DOI: 10.1126/stke.2252004TW103

When mammals are infected with potentially deadly bacteria, the microbes wage a signaling battle with the macrophages of the host's innate immune system. When Toll-like receptors on the macrophages detect molecules of bacterial origin, this stimulates the macrophages to dispense with the invading cells. The anthrax bacterium, B. anthracis, counters by producing lethal toxin, which prevents antiapoptotic signaling through the p38 mitogen-activated protein kinase. Furthermore, Toll-like receptors can produce both antiapoptotic and apoptotic signals, and Hsu et al. now report that the signals generated by Toll-like receptor 4 (TLR4) can turn in favor of the invaders by promoting apoptosis of stimulated macrophages. The authors found that macrophages exposed to an inhibitor of p38 (mimicking a lethal toxin) and to heat-inactivated B. anthracis underwent apoptosis in a manner dependent on the presence of TLR4. The TLR4 signal that promoted cell death was diminished in cells lacking the double-stranded RNA-responsive kinase PKR, a known mediator of TLR signaling, or in cells lacking the adaptor protein TRIF, which links TLR4 to activation of PKR. PKR in turn can inhibit protein synthesis by phosphorylating eukaryotic translation initiation factor 2α (eIF2α). Indeed, eIF2α appeared to be a key target of PKR, because cells from knockin mice expressing a mutant form of eIF2α in which the PKR phosphorylation site was disrupted were less sensitive to a combination of lipopolysaccharide (a bacterial cell wall component) and p38 inhibitor than were wild-type cells. The authors note that inhibition of PKR provides a potential therapeutic strategy to thwart bacteria like B. anthracis that can otherwise use auxiliary factors like lethal toxin to turn TLR signals to deadly effect.

L.-C. Hsu, J. M. Park, K. Zhang, J.-L. Luo, S. Maeda, R. J. Kaufman, L. Eckmann, D. G. Guiney, M. Karin, The protein kinase PKR is required for macrophage apoptosis after activation of Toll-like receptor 4. Nature 428, 341-345 (2004). [Online Journal]