Abstract

Innate Immunity employs so-called pattern recognition receptors (PRRs) for initiating inflammation as a step towards resolving both infectious and sterile insults. These pathways are triggered by microbe-associated (MAMPs) or danger-associated (DAMPs) molecular patterns, respectively. We recently discovered two novel MAMP and DAMP pathways. Firstly, we found the secreted host enzyme, CHIT1 , to convert the inert polymeric MAMP and fungal cell wall/allergen component, chitin, into diffusible chitin oligomers that can be sensed by TLR1 -TLR2 co-receptor/receptor heterodimers, a process promoted by lipopolysaccharide binding protein (LBP) and CD14 . Our study shows the existence of an inducible system of MAMP generation within the human host that enables contact-independent immune activation by diffusible MAMP ligands with striking similarity to the plant kingdom. Secondly, we identified naRNA (NET-associated RNA ), as a new canonical component of neutrophil extracellular traps (NETs) and a potent disease-exacerbating novel DAMP . naRNA, in complex with the host antimicrobial peptide LL37 , propagated a self-amplifying cycle of NET formation in naïve neutrophils, dependent on TLR8 in humans and Tlr13 in mice, in vitro and in vivo. Our data not only highlight naRNA as a novel DAMP driving immune activation; naRNA also provides a molecular link between the reported respective pathophysiological roles of NETs and extracellular RNA in multiple diseases, and suggest blockade of TLR -mediated RNA sensing as a potential new interventional target.