The Journal of Experimental Medicine
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Published online
doi:10.1084/jem.20072152
The Journal of Experimental Medicine, Vol. 205, No. 3, 685-698
The Rockefeller University Press, 0022-1007 $30.00
© Conus et al.
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ARTICLE

 Caspase-8 is activated by cathepsin D initiating neutrophil apoptosis during the resolution of inflammation

Sébastien Conus1, Remo Perozzo2, Thomas Reinheckel3, Christoph Peters3, Leonardo Scapozza2, Shida Yousefi1, and Hans-Uwe Simon1

1 Institute of Pharmacology, University of Bern, 3010 Bern, Switzerland
2 Pharmaceutical Biochemistry Group, School of Pharmaceutical Sciences, Ecole de Pharmacie Genève-Lausanne, University of Geneva, 1211 Geneva 4, Switzerland
3 Institute of Molecular Medicine and Cell Research, University of Freiburg, 79104 Freiburg, Germany

CORRESPONDENCE Hans-Uwe Simon: hus{at}pki.unibe.ch

In the resolution of inflammatory responses, neutrophils rapidly undergo apoptosis. We describe a new proapoptotic pathway in which cathepsin D directly activates caspase-8. Cathepsin D is released from azurophilic granules in neutrophils in a caspase-independent but reactive oxygen species–dependent manner. Under inflammatory conditions, the translocation of cathepsin D in the cytosol is blocked. Pharmacological or genetic inhibition of cathepsin D resulted in delayed caspase activation and reduced neutrophil apoptosis. Cathepsin D deficiency or lack of its translocation in the cytosol prolongs innate immune responses in experimental bacterial infection and in septic shock. Thus, we identified a new function of azurophilic granules that is in addition to their role in bacterial defense mechanisms: to regulate the life span of neutrophils and, therefore, the duration of innate immune responses through the release of cathepsin D.

Abbreviations used: CA, CA-074-ME; CGD, chronic granulomatous disease; DPI, diphenyleneiodonium; MPO, myeloperoxidase; NADPH, nicotinamide adenine dinucleotide phosphate; PepA, pepstatin A; PI, propidium iodide; PS, phosphatidylserine; ROS, reactive oxygen species; SCLC, small cell lung carcinoma.


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