Caspase-8 is activated by cathepsin D initiating neutrophil apoptosis during the resolution of inflammation.
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.
Conus
Sébastien
S
Institute of Pharmacology, University of Bern, 3010 Bern, Switzerland.
Perozzo
Remo
R
Reinheckel
Thomas
T
Peters
Christoph
C
Scapozza
Leonardo
L
Yousefi
Shida
S
Simon
Hans-Uwe
HU
D000818:Animals; D017209:Apoptosis / Q000276:immunology / Q000502:physiology*; D053181:Caspase 8 / Q000378:metabolism*; D002401:Cathepsin B / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D002402:Cathepsin D / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D045304:Cytochromes c / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D007113:Immunity, Innate; D066298:In Vitro Techniques; D007249:Inflammation / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012772:Shock, Septic / Q000097:blood / Q000276:immunology
D017382:Reactive Oxygen Species; D045304:Cytochromes c; C505526:Casp8 protein, mouse; D053181:Caspase 8; D002401:Cathepsin B; D002402:Cathepsin D