Cathelicidin is a “fire alarm”, generating protective NLRP3-dependent airway epithelial cell inflammatory responses during infection with Pseudomonas aeruginosa

Brodsky, I. E. et al. (2019) Cathelicidin is a “fire alarm”, generating protective NLRP3-dependent airway epithelial cell inflammatory responses during infection with Pseudomonas aeruginosa. PLoS Pathogens, 15(4), e1007694. (doi: 10.1371/journal.ppat.1007694) (PMID:30978238) (PMCID:PMC6481867)

Abstract

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.

• Item Type: Articles
• Additional Information: DJD was funded by a Medical Research Council senior non-clinical fellowship (G1002046). DB was funded by a Medical Research Council project grant (MR/N029992/1). AGR was funded by a Medical Research Council programme grant (MR/K013386/1). Funder website: https://mrc.ukri.org/.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Finlayson, Mrs Lisa

Creator Roles

Young, L.: Investigation

• Authors: Brodsky, I. E., McHugh, B. J., Wang, R., Li, H.-N., Beaumont, P. E., Kells, R., Stevens, H., Young, L., Rossi, A. G., Gray, R. D., Dorin, J. R., Gwyer Findlay, E. L., Brough, D., and Davidson, D. J.
• College/School: College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
• Journal Name: PLoS Pathogens
• Publisher: Public Library of Science
• ISSN: 1553-7366
• ISSN (Online): 1553-7374
• Published Online: 12 April 2019
• Copyright Holders: Copyright © 2019 McHugh et al.
• First Published: First published in PLoS Pathogens 15(4): e1007694
• Publisher Policy: Reproduced under a Creative Commons License