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

Conus, Sébastien; Perozzo, Remo; Reinheckel, Thomas; Peters, Christoph; Scapozza, Leonardo; Yousefi, Shida; Simon, Hans-Uwe (2008). Caspase-8 is activated by cathepsin D initiating neutrophil apoptosis during the resolution of inflammation. Journal of experimental medicine, 205(3), pp. 685-698. New York, N.Y.: Rockefeller University Press 10.1084/jem.20072152

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Pharmacology

UniBE Contributor:

Conus, Sébastien and Simon, Hans-Uwe

ISSN:

0022-1007

ISBN:

18299403

Publisher:

Rockefeller University Press

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 14:54

Last Modified:

08 Jun 2016 10:42

Publisher DOI:

10.1084/jem.20072152

PubMed ID:

18299403

Web of Science ID:

000254173100017

URI:

https://boris.unibe.ch/id/eprint/23057 (FactScience: 38753)

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