Complexes of RNA and the antimicrobial peptide, LL37, trigger TLR-mediated cytokine release from psoriasis neutrophils

Psoriasis is an inflammatory autoimmune disease characterized by skin lesions showing strong immune cells infiltration and high levels of the antimicrobial peptide, LL37. LL37 binds RNA and DNA and these complexes trigger Toll-like receptors (TLRs) and subsequent interferon release from plasmacytoid dendritic cells. Polymorphonuclear leukocytes (PMNs) are abundant in psoriatic skin and are primary sources for LL37, extracellular nucleic acids and inflammatory cytokines. We hypothesized that LL37-nucleic acid complexes sustain a self-amplifying inflammatory loop via TLR signaling in PMNs but this hypothesis has not been investigated. We here show that LL37 potentiated TLR8-mediated IL-8 release by PMNs in response to synthetic, human and bacterial RNA, by promoting its uptake. Additionally, RNA complexed to LL37 prompted PMNs to produce TNF, IL-6 and IL-1β, as well as the chemoattractants IL-16 and MIP-1β. Interestingly, in PMNs from psoriasis patients, TLR-triggered cytokine and chemokine release and constitutive LL37 secretion were generally elevated compared to PMNs from healthy donors and RNA triggered IL-8 even in the absence of exogenous LL37. Finally, we observed that inhibitory oligodeoxynucleotides (iODNs), previously used to block TLR7 and TLR9 responses, prevented the TLR response of PMNs to RNA-LL37 complexes. Collectively, our data suggest that in psoriatic lesions RNA-LL37-driven PMN activation may contribute to a vicious cycle of inflammation and immune cells attraction, and that TLR blockade could be used to limit PMN-mediated inflammation and immune cell infiltration in this context.