The role of the human cathelicidin LL-37 as an immunomodulator in infectious lung disease. (360G-Wellcome-078265_Z_05_Z)

Cationic host defence peptides (CHDP) are key components of innate defences, recently proposed as potent immunomodulators. LL-37 is a CHDP produced by neutrophils and epithelial cells, and upregulated during infection and inflammation. I have discovered that LL-37 promotes epithelial cell apoptosis,but inhibits neutrophil apoptosis. The differential effects of LL-37 and the underlying mechanisms will be characterised and contrasted in vitro, examining: a) priming of beneficial airway epithelial cell apoptosis through altered Bcl2 family gene expression, as a defence against infection, and b) inhibition of neutrophil apoptosis through activation of MAPK and NFkB pathways, promoting bacterial killing. I propose that these effects of LL-37 enhance innate host defence in acute infectious lung disease, but contribute to disease pathogenesis in chronic exposure, such as occurs in cystic fibrosislung disease. The in vivo contribution of these LL-37-mediated effects to the clearance of pulmonary Pseudomonas aeruginosa infection in murine models will be defined, and the significance of chronic LL-37 exposure to cystic fibrosis lung disease pathogenesis will be determined. A clear understanding of these immunomodulatory effects of LL-37 in vitro and in vivo is required to establish physiological significance and enable appropriately targeted development of synthetic derivatives as therapeutics for antibiotic-resistant infections.