Pulmonary
infections are a major global cause of morbidity, exacerbated by an increasing threat from
antibiotic-resistant pathogens. In this context, therapeutic interventions aimed at protectively modulating host responses, to enhance defence against
infection, take on ever greater significance. Pseudomonas aeruginosa is an important multidrug-resistant, opportunistic respiratory pathogen, the clearance of which can be enhanced in vivo by the innate immune modulatory properties of antimicrobial host defence
peptides from the
cathelicidin family, including human LL-37. Initially described primarily as bactericidal agents,
cathelicidins are now recognised as multifunctional antimicrobial
immunomodulators, modifying host responses to pathogens, but the key mechanisms involved in these protective functions are not yet defined. We demonstrate that P. aeruginosa
infection of airway epithelial cells promotes extensive infected cell internalisation of LL-37, in a manner that is dependent upon epithelial cell interaction with live bacteria, but does not require bacterial
Type 3 Secretion System (T3SS). Internalised LL-37 acts as a second signal to induce
inflammasome activation in airway epithelial cells, which, in contrast to myeloid cells, are relatively unresponsive to P. aeruginosa. We demonstrate that this is mechanistically dependent upon
cathepsin B release, and NLRP3-dependent activation of
caspase 1. These result in LL-37-mediated release of IL-1β and
IL-18 in a manner that is synergistic with P. aeruginosa
infection, and can induce
caspase 1-dependent death of infected epithelial cells, and promote neutrophil chemotaxis. We propose that
cathelicidin can therefore act as a second signal, required by P. aeruginosa infected epithelial cells to promote an
inflammasome-mediated altruistic cell death of
infection-compromised epithelial cells and act as a "fire alarm" to enhance rapid escalation of protective inflammatory responses to an uncontrolled
infection. Understanding this novel modulatory role for
cathelicidins, has the potential to inform development of novel therapeutic strategies to
antibiotic-resistant pathogens, harnessing innate immunity as a complementation or alternative to current interventions.