Effect of antimicrobial proteins/alarmins on DNA mediated activation of pDC and inflammation. (45.11)

Abstract

Abstract Plasmacytoid dendritic cells (pDCs) commonly known as IFN-α producing cells, detect microbial nucleic acids via endosomal Toll-like receptor (TLR)-7 and TLR-9. Antimicrobial peptides (AMPs) like LL37, derived from neutrophil granules and keratinocytes enhance the production of IFN-α by pDCs by forming complexes with self nucleic acids by converting them into a potent trigger of pDC activation (Lande K. et al. Nature 449-564, 2007). This report led us to study the effect of other antimicrobial proteins stored in neutrophils or produced by keratinocytes during inflammation. In this study we present opposing effects of two antimicrobial alarmins; Human Beta Defensin 3 (HBD3) and Lactoferrin (LF), on IFN alpha production by pDCs. HBD3, an epithelial cell product and a host defense molecule, acts as a potent activator of pDCs by promoting DNA induced IFN alpha production by pDC and subsequent activation of bystander myeloid cells. Hence HBD3 may be important contributor to ongoing inflammation and can exacerbate inflammation in autoimmune pathologies like psoriasis. On the other hand LF inhibited DNA induced IFN alpha production by preventing uptake of both self and CpG DNA indicating that it acts as a scavenger molecule for DNA motifs, potentially reducing the undesirable effects of high levels of IFN-α. We therefore propose that a delicate balance between different AMPs present at inflammatory sites determines the outcome of IFN-mediated pDC activation.