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

Sébastien Conus, et al. 2008. J. Exp. Med. 205, 685-698

Student: Chia-Hui Huang (黃佳慧)             Time: 15:00~16:00, Nov. 5, 2008

Commentator: Chiou-Feng Lin (林秋烽老師)         Place: Room 601

Abstract

        Neutrophil apoptosis is considered essential for the resolution of an inflammatory process. The induction of neutrophil apoptosis during the resolution of an innate immune response can be mimicked in vitro by culturing the cells in the absence of sufficient amounts of survival factors, a process that is called spontaneous neutrophil apoptosis. Caspase-8 cleavage proceeded caspase-3 cleavage both in spontaneous and Fas receptor-mediated apoptosis [1], but it remains unclear how caspases are activated in neutrophils. Cathepsin D is released from azurophilic granules in neutrophils, but the release of cathepsin D in the cytosol is blocked under inflammatory condition. In previous research, cathepsin D can activate Bax, resulting in AIF and cytochrome c release from mitochondia and it also can trigger caspase-dependent apoptosis [2, 3]. To resolve the role of whether cathepsin D is involved in neutrophil apoptosis, the authors used pepstatin A (PepA) to specifically inactivate cathepsin D. The inhibition of cathepsin D delayed the activation of caspase and reduced neutrophil apoptosis. In cathepsin D^-/- mice intraperitoneally injected with low-dose LPS, the neutrophils were apoptosis resistant and it prolonged the duration of inflammation. Furthermore, ROS-deficient neutrophils delayed cathepsin D release from azurophilic granules to cytosol and delayed neutrophil apoptosis. Taken together, the authors suggested that the release of cathepsin D from azurophilic granules was in a reactive oxygen species-dependent manner, leading to caspase-8 activation, and it also regulated neutrophil apoptosis and the duration of innate immune responses.

Reference:

1.      Altznauer, F., et al. 2004. Calpain-1 regulates Bax and subsequent Smac-dependent caspase-3 activation in neutrophil apoptosis. J. Biol. Chem. 279: 5947 – 5957.

2.      Bidere , N., et al. 2003 . Cathepsin D triggers Bax activation, resulting in selective apoptosis-inducing factor (AIF) relocation in T lymphocytes entering the early commitment phase to apoptosis. J. Biol. Chem. 278: 31401 – 31411.

3.      Roberg, K., Kågedal, K., and Öllinger, K. 2002. Microinjection of cathepsin D induces caspase-dependent apoptosis in fibroblasts. Am. J. Pathol. 161: 89 – 96.