RNA-antimicrobial peptide complexes activate a self-sustaining TLR- and NETosis-mediated cycle of neutrophil activation

Psoriasis is an inflammatory autoimmune disease characterized by skin lesions showing strong neutrophil (PMN) infiltration and high levels of the antimicrobial peptide, LL37, but the role of PMN in this context is unclear. We here show that primary human PMN, especially PMN from psoriasis patients, not only respond via TLR8 to human and bacterial RNA complexed to LL37 with cytokine, chemokine and neutrophil extracellular trap (NET) release; they also themselves release additional RNA and LL37, which were abundant in psoriasis patient skin, in response to activation by the same complex. RNA-LL37 complexes can thus fuel a PMN-mediated and self-sustaining inflammatory loop that may represent an unexpected early initiating or amplifying event in psoriasis. Given that TLR inhibitory oligodeoxynucleotides (iODNs) prevent the activation of PMNs by RNA-LL37 complexes in vitro, our study also highlights TLR blockade as a potential therapeutic intervention strategy in psoriasis.