![]() ![]() Mcl-1 expression is regulated by transcription and translation. The shift from apoptosis resistance is determined by the decline in abundance of the anti-apoptotic protein Mcl-1. Macrophage function is regulated by induction of apoptosis during pneumococcal infection. During the initial stages of pneumococcal infection, macrophages are largely responsible for bacterial clearance and determine the initiation as well as the later resolution of the inflammatory response. Streptococcus pneumoniae, the pneumococcus, is the most prevalent cause of community-acquired pneumonia. To accommodate their opposing roles in long-term tissue homeostasis and short-term immune responses, tissue macrophages, such as alveolar macrophages, are long-lived in the basal state, , yet can activate a variety of death pathways upon pathogen encounter. Macrophages must also coordinate the innate response to microorganisms that penetrate sterile environments such as the lower respiratory tract. Macrophages are essential for the maintenance of tissue homeostasis, as they remove dying and dead cells. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Ĭompeting interests: The authors have declared that no competing interests exist. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.įunding: The authors' work is supported by a Wellcome Trust ( Senior Clinical Fellowship to DHD, #076945 a British Lung Foundation ( Fellowship to HMM, #F05/7 a BBSRC ( grant, #BB/D005469/1 to BC and by grants from the Wellcome Trust and Medical Research Council ( to TJM. Received: MaAccepted: DecemPublished: January 27, 2011Ĭopyright: © 2011 Bewley et al. PLoS Pathog 7(1):Įditor: Vojo Deretic, University of New Mexico, United States of America (2011) A Cardinal Role for Cathepsin D in Co-Ordinating the Host-Mediated Apoptosis of Macrophages and Killing of Pneumococci. 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.Ĭitation: Bewley MA, Marriott HM, Tulone C, Francis SE, Mitchell TJ, Read RC, et al. 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. 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. 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. Cathepsin D activation is required for permeabilization of mitochondria, an organelle implicated in apoptosis induction. Pneumococcal exposure activates a phagolysosomal enzyme, cathepsin D, which induces apoptosis. We show that the cell structure containing ingested bacteria, the phagolysosome, becomes permeabilized early in the death process. ![]() We have investigated the mechanism of apoptosis in macrophages exposed to pneumococci, the commonest cause of bacterial pneumonia. In macrophages, induction of apoptosis enhances bacterial killing when macrophages' initial killing capacity is exhausted. ![]() Tissue macrophages frequently undergo a program of cell death, termed apoptosis, following sustained ingestion and killing of bacteria. 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. Mice bearing a cathepsin D −/− hematopoietic system demonstrated reduced macrophage apoptosis in vivo, with decreased clearance of pneumococci and enhanced recruitment of neutrophils to control pulmonary infection. Inhibition of cathepsin D had no effect on early bacterial killing but inhibited the late phase of apoptosis-associated killing of pneumococci in vitro. As a result of cathepsin D activation, Mcl-1 interacted with its ubiquitin ligase Mule and expression declined. Pharmacological inhibition or knockout of cathepsin D during pneumococcal infection blocked macrophage apoptosis. 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. ![]() The bactericidal function of macrophages against pneumococci is enhanced by their apoptotic demise, which is controlled by the anti-apoptotic protein Mcl-1. ![]()
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