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A Cardinal Role for Cathepsin D in Co-Ordinating the Host-Mediated Apoptosis of Macrophages and Killing of Pneumococci
- Source :
- Bewley, M A, Marriott, H M, Tulone, C, Francis, S E, Mitchell, T J, Read, R C, Chain, B, Kroemer, G, Whyte, M K B & Dockrell, D 2011, ' A Cardinal Role for Cathepsin D in Co-Ordinating the Host-Mediated Apoptosis of Macrophages and Killing of Pneumococci ', PLoS Pathogens, vol. 7, no. 1, 1001262 . https://doi.org/10.1371/journal.ppat.1001262, PLoS Pathogens, PLoS Pathogens, Vol 7, Iss 1, p e1001262 (2011)
- Publication Year :
- 2011
-
Abstract
- The bactericidal function of macrophages against pneumococci is enhanced by their apoptotic demise, which is controlled by the anti-apoptotic protein Mcl-1. Here, we show that lysosomal membrane permeabilization (LMP) and cytosolic translocation of activated cathepsin D occur prior to activation of a mitochondrial pathway of macrophage apoptosis. Pharmacological inhibition or knockout of cathepsin D during pneumococcal infection blocked macrophage apoptosis. As a result of cathepsin D activation, Mcl-1 interacted with its ubiquitin ligase Mule and expression declined. Inhibition of cathepsin D had no effect on early bacterial killing but inhibited the late phase of apoptosis-associated killing of pneumococci in vitro. Mice bearing a cathepsin Dā/ā hematopoietic system demonstrated reduced macrophage apoptosis in vivo, with decreased clearance of pneumococci and enhanced recruitment of neutrophils to control pulmonary infection. These findings establish an unexpected role for a cathepsin D-mediated lysosomal pathway of apoptosis in pulmonary host defense and underscore the importance of apoptosis-associated microbial killing to macrophage function.<br />Author Summary Tissue macrophages frequently undergo a program of cell death, termed apoptosis, following sustained ingestion and killing of bacteria. In macrophages, induction of apoptosis enhances bacterial killing when macrophages' initial killing capacity is exhausted. We have investigated the mechanism of apoptosis in macrophages exposed to pneumococci, the commonest cause of bacterial pneumonia. We show that the cell structure containing ingested bacteria, the phagolysosome, becomes permeabilized early in the death process. Pneumococcal exposure activates a phagolysosomal enzyme, cathepsin D, which induces apoptosis. Cathepsin D activation is required for permeabilization of mitochondria, an organelle implicated in apoptosis induction. Cathepsin D reduces levels of a negative regulator of apoptosis in macrophages, Mcl-1, by enhancing its association with an enzyme, which mediates its degradation. The importance of these findings was confirmed in a bone marrow transplant model in which mice either received bone marrow from mice containing or lacking the cathepsin D gene. This model showed that reduced apoptosis of alveolar macrophages occurred when cathepsin D was lacking, and that this impaired clearance of pneumococci in the mouse lung. We conclude that during bacterial challenge, lysosomal permeabilization and cathepsin D activation triggers a novel death pathway, in a timely fashion, linking bacterial killing to apoptosis induction.
- Subjects :
- PULMONARY INFECTION
Cathepsin D
STREPTOCOCCUS-PNEUMONIAE
Apoptosis
NEUTROPHIL RECRUITMENT
Mitochondrion
Respiratory Medicine/Respiratory Infections
Infectious Diseases/Bacterial Infections
Mice
Cytosol
0302 clinical medicine
LYSOSOMAL MEMBRANE PERMEABILIZATION
Phagosomes
Macrophage
Biology (General)
OXIDATIVE STRESS
Bone Marrow Transplantation
Cathepsin S
Mice, Knockout
0303 health sciences
Cell Biology/Cellular Death and Stress Responses
HUMAN ALVEOLAR MACROPHAGES
3. Good health
Cell biology
Ubiquitin ligase
Streptococcus pneumoniae
030220 oncology & carcinogenesis
Host-Pathogen Interactions
Female
Research Article
Programmed cell death
QH301-705.5
Immunology
Bone Marrow Cells
Biology
Microbiology
03 medical and health sciences
Cell Line, Tumor
Virology
Genetics
Animals
Humans
Molecular Biology
030304 developmental biology
Cathepsin
NITRIC-OXIDE
Macrophages
Intracellular Membranes
RC581-607
BONE-MARROW-TRANSPLANTATION
Mice, Inbred C57BL
CELL-DEATH
Immunology/Immune Response
biology.protein
Parasitology
Immunologic diseases. Allergy
MCL-1
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Bewley, M A, Marriott, H M, Tulone, C, Francis, S E, Mitchell, T J, Read, R C, Chain, B, Kroemer, G, Whyte, M K B & Dockrell, D 2011, ' A Cardinal Role for Cathepsin D in Co-Ordinating the Host-Mediated Apoptosis of Macrophages and Killing of Pneumococci ', PLoS Pathogens, vol. 7, no. 1, 1001262 . https://doi.org/10.1371/journal.ppat.1001262, PLoS Pathogens, PLoS Pathogens, Vol 7, Iss 1, p e1001262 (2011)
- Accession number :
- edsair.doi.dedup.....03e0c9a7d91f562b66a263c168d4bb02