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

Conus, Sébastien; Perozzo, Remo; Reinheckel, Thomas; Peters, Christoph; Scapozza, Léonardo; Yousefi, Shída; Simon, Hans‐Uwe

doi:10.1083/jcb1805oia14

Cited by 34 publications

(39 citation statements)

References 21 publications

(33 reference statements)

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“…Interestingly, anti-apoptotic mitochondrial proteins such as Bcl-2, Bcl-xL and Mcl-1 are degraded by lysosomal cathepsins, which, combined with cathepsin-mediated Bid activation, can trigger MMP and apoptosis (Droga-Mazovec et al, 2008). Cathepsins D and L have also been shown to directly activate caspase-8 in some cell models (Baumgartner et al, 2007; Conus et al, 2008), which may result in Bid cleavage. Our current and previous results indicate that PA-LTx in NGFDPC12 cells is cathepsin L-dependent and involves the activation of caspase-8 (Ulloth et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Lipotoxicity-mediated cell dysfunction and death involve lysosomal membrane permeabilization and cathepsin L activity

et al. 2010

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Lipotoxicity, which is triggered when cells are exposed to elevated levels of free fatty acids, involves cell dysfunction and apoptosis and is emerging as an underlying factor contributing to various pathological conditions including disorders of the central nervous system and diabetes. We have shown that palmitic acid (PA)-induced lipotoxicity (PA-LTx) in nerve growth factor-differentiated PC12 (NGFDPC12) cells is linked to an augmented state of cellular oxidative stress (ASCOS) and apoptosis, and that these events are inhibited by docosahexanoic acid (DHA). The mechanisms of PA-LTx in nerve cells are not well understood, but our previous findings indicate that it involves ROS generation, mitochondrial membrane permeabilization (MMP), and caspase activation. The present study used nerve growth factor differentiated PC12 cells (NGFDPC12 cells) and found that lysosomal membrane permeabilization (LMP) is an early event during PA-induced lipotoxicity that precedes MMP and apoptosis. Cathepsin L, but not cathepsin B, is an important contributor in this process since its pharmacological inhibition significantly attenuated LMP, MMP, and apoptosis. In addition, co-treatment of NGFDPC12 cells undergoing lipotoxicity with DHA significantly reduced LMP, suggesting that DHA acts by antagonizing upstream signals leading to lysosomal dysfunction. These results suggest that LMP is a key early mediator of lipotoxicity, and underscore the value of interventions targeting upstream signals leading to LMP for the treatment of pathological conditions associated with lipotoxicity.

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Section: Discussionmentioning

confidence: 99%

Lipotoxicity-mediated cell dysfunction and death involve lysosomal membrane permeabilization and cathepsin L activity

et al. 2010

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“…Cells were analysed with FACS Calibur (Becton Dickinson, Franklin Lakes, NJ). Neutrophils were identified by forward‐scatter versus side‐scatter characteristics and by Ly6G staining . Data analysis was performed with Cell Quest software (Becton Dickinson, Franklin Lakes, NJ).…”

Section: Methodsmentioning

confidence: 99%

Low‐molecular‐mass hyaluronan induces pulmonary inflammation by up‐regulation of Mcl‐1 to inhibit neutrophil apoptosis via PI3K/Akt1 pathway

Zhao

Zhang

2018

Immunology

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Although low-molecular-mass hyaluronan (LMMHA) has been implicated in pulmonary inflammatory diseases, the signalling pathway of LMMHA (200 000 molecular weight) that initiates the inflammatory response in lung is still unknown. In this study, we evaluate the role of phosphoinositide 3-kinase (PI3K) and its downstream signalling pathway in LMMHA-induced lung inflammatory responses. Our results indicate that pharmacological inhibition of PI3K or genetic deletion of Akt1 enhances neutrophil apoptosis, attenuates neutrophil influx into the lungs of mice and diminishes the expression of pro-inflammatory factors such as interleukin-6, keratinocyte cell-derived chemokine and pro-matrix metalloproteinase-9 in bronchoalveolar lavage fluid after intratracheal administration of LMMHA. More importantly, we found that PI3K/Akt1 participates in LMMHA-induced inflammatory responses, which are mainly mediated by the myeloid leukaemia cell differentiation protein (Mcl-1). Our study suggests that LMMHA induced significantly increased levels of inflammatory factors in bronchoalveolar lavage fluid and activation of the PI3K/Akt1 pathway, which up-regulates the expression of the anti-apoptotic protein Mcl-1 and inhibits the activation of caspase-3, thereby suppressing neutrophil apoptosis to trigger lung inflammation. These findings reveal a novel molecular mechanism underlying sterile inflammation and provides a new potential target for the treatment of pulmonary disease.

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“…Despite some reports to the contrary, a major role in lysosome‐mediated apoptotic cell death has been attributed to cathepsin D, and a few molecular apoptotic targets of this protease have been described. These include the pro‐apoptotic Bcl‐2 proteins Bax and Bid ( in vitro up to a pH of 6.2) , and the initiator caspase 8 in neutrophil apoptosis (Fig. ).…”

Section: Cathepsins As Major Effectors Of Lmpmentioning

confidence: 99%

Lysosomal proteins in cell death and autophagy

2015

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Nearly 60 years ago, lysosomes were first described in the laboratory of Christian de Duve, a discovery that significantly contributed to him being awarded a share of the 1974 Nobel Prize in Physiology or Medicine for elucidating ‘the structural and functional organization of the cell’. Initially thought of as a simple waste degradation facility of the cell, these organelles recently emerged as signalling centres with connections to major cellular processes. This review provides an overview of the many roles of lysosomal proteins in two of these processes: cell death and autophagy. We discuss both resident lysosomal proteins as well those that temporarily associate with lysosomes to influence autophagy and cell death pathways. Particular focus is given to studies in mammalian cells and in vivo systems.

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

Cited by 34 publications

References 21 publications

Lipotoxicity-mediated cell dysfunction and death involve lysosomal membrane permeabilization and cathepsin L activity

Lipotoxicity-mediated cell dysfunction and death involve lysosomal membrane permeabilization and cathepsin L activity

Low‐molecular‐mass hyaluronan induces pulmonary inflammation by up‐regulation of Mcl‐1 to inhibit neutrophil apoptosis via PI3K/Akt1 pathway

Lysosomal proteins in cell death and autophagy

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