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Abstract
Cationic host defense peptides are key, evolutionarily conserved components of the innate immune system. The human cathelicidin LL-37 is an important cationic host defense peptide up-regulated in infection and inflammation, specifically in the human lung, and was shown to enhance the pulmonary clearance of the opportunistic pathogen Pseudomonas aeruginosa in vivo by as yet undefined mechanisms. In addition to its direct microbicidal potential, LL-37 can modulate inflammation and immune mechanisms in host defense against infection, including the capacity to modulate cell death pathways. We demonstrate that at physiologically relevant concentrations of LL-37, this peptide preferentially promoted the apoptosis of infected airway epithelium, via enhanced LL-37-induced mitochondrial membrane depolarization and release of cytochrome c, with activation of caspase-9 and caspase-3 and induction of apoptosis, which only occurred in the presence of both peptide and bacteria, but not with either stimulus alone. This synergistic induction of apoptosis in infected cells was caspase-dependent, contrasting with the caspase-independent cell death induced by supraphysiologic levels of peptide alone. We demonstrate that the synergistic induction of apoptosis by LL-37 and Pseudomonas aeruginosa required specific bacteria-epithelial cell interactions with whole, live bacteria, and bacterial invasion of the epithelial cell. We propose that the LL-37-mediated apoptosis of infected, compromised airway epithelial cells may represent a novel inflammomodulatory role for this peptide in innate host defense, promoting the clearance of respiratory pathogens.
Highlights
We demonstrate that the synergistic induction of apoptosis by LL-37 and Pseudomonas aeruginosa required specific bacteria–epithelial cell interactions with whole, live bacteria, and bacterial invasion of the epithelial cell
To determine the capacity of LL-37 to induce cell death in infected airway epithelial cells, the human bronchial epithelial cell line 16HBE14o2 was infected with P. aeruginosa PAO1, with or without concurrent exposure to LL-37
Total cell counts demonstrated no loss of cells during analysis. To confirm these observation in nontransformed cells, primary human airway epithelial cells were used, and demonstrated the same response, with significant cell death induced in the presence of physiologically inflammatory levels of LL-37 only when infected with P. aeruginosa PAO1 (Figure 1B)
Summary
We demonstrate that at physiologically relevant concentrations of LL-37, this peptide preferentially promoted the apoptosis of infected airway epithelium, via enhanced LL-37–induced mitochondrial membrane depolarization and release of cytochrome c, with activation of caspase-9 and caspase-3 and induction of apoptosis, which only occurred in the presence of both peptide and bacteria, but not with either stimulus alone. Studies using a mouse model deficient in cathelin-related antimicrobial peptide (mCRAMP), the murine ortholog of LL-37, demonstrated increased susceptibility to infections of the skin, gastrointestinal system, urinary tract, and cornea [5,6,7,8] Despite this clear evidence of a critical role for cathelicidin expression in innate defense against infection, the relative roles of the microbicidal and immunomodulatory activities of this peptide remain unclear
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