The bactericidal function of macrophages against Brush Roller Drive Gear 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 BOSCH NBS533BB0B Electric Built-under Double Oven - Black 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.