A Cardinal Role for Cathepsin D in Co-Ordinating the Host-Mediated Apoptosis of Macrophages and Killing of Pneumococci

PLoS Pathogens

Moira K. B. Whyte¹  Calogero Tulone²  Benny Chain²  Guido Kroemer³  Timothy J. Mitchell⁴  Martin A. Bewley⁵  Sheila E. Francis⁵  Robert C. Read⁵  Helen M. Marriott⁵  David H. Dockrell⁶ 

[1] Centre de Recherche des Cordeliers, Paris, France;Division of Infection and Immunity, University College London, London, United Kingdom;INSERM U848, Metabolomics Platform, Institut Gustave Roussy, Villejuif, France;Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom;Medical School, University of Sheffield, Sheffield, United Kingdom;Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France

关键词: Apoptosis;    Macrophages;    Cell differentiation;    Lysosomes;    Neutrophils;    Alveolar macrophages;    Mitochondria;    Bone marrow transplantation;   

DOI  :  10.1371/journal.ppat.1001262

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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 D−/− 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.

【 授权许可】

CC BY