Self-RNA–antimicrobial peptide complexes activate human dendritic cells through TLR7 and TLR8

TLDR

In psoriasis, the antimicrobial peptide LL37 enables plasmacytoid dendritic cells to sense self‑DNA via endosomal TLR9, while normally extracellular self‑DNA and self‑RNA are kept inert by endosomal sequestration of nucleic‑acid TLRs. The study investigates whether LL37 also binds extracellular self‑RNA and contributes to dendritic‑cell activation in psoriasis. LL37 complexes with self‑RNA from dying cells, protects it, delivers it to endosomal TLR7 in pDCs (inducing IFN‑α) and to TLR8 in myeloid DCs (inducing TNF‑α, IL‑6 and maturation), and these complexes are found in psoriatic skin, revealing a mechanism for auto‑inflammatory responses.

Abstract

Dendritic cell (DC) responses to extracellular self-DNA and self-RNA are prevented by the endosomal seclusion of nucleic acid–recognizing Toll-like receptors (TLRs). In psoriasis, however, plasmacytoid DCs (pDCs) sense self-DNA that is transported to endosomal TLR9 upon forming a complex with the antimicrobial peptide LL37. Whether LL37 also interacts with extracellular self-RNA and how this may contribute to DC activation in psoriasis is not known. Here, we report that LL37 can bind self-RNA released by dying cells, protect it from extracellular degradation, and transport it into endosomal compartments of DCs. In pDC, self-RNA–LL37 complexes activate TLR7 and, like self-DNA–LL37 complexes, trigger the secretion of IFN-α without inducing maturation or the production of IL-6 and TNF-α. In contrast to self-DNA–LL37 complexes, self-RNA–LL37 complexes also trigger the activation of classical myeloid DCs (mDCs). This occurs through TLR8 and leads to the production of TNF-α and IL-6, and the differentiation of mDCs into mature DCs. We also found that self-RNA–LL37 complexes are present in psoriatic skin lesions and are associated with mature mDCs in vivo. Our results demonstrate that the cationic antimicrobial peptide LL37 converts self-RNA into a trigger of TLR7 and TLR8 in human DCs, and provide new insights into the mechanism that drives the auto-inflammatory responses in psoriasis.