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¹ Departments of Immunology, ² Melanoma Medical Oncology, and ³ Dermatology, The University of Texas M.D. Anderson Cancer Center, TX 77030
⁴ Graduate School of Biomedical Sciences, University of Texas at Houston, Houston, TX 77030
⁵ Department of Dermatology, Heinrich-Heine University, Dusseldorf 40225, Germany
⁶ Dynavax Technologies Corporation, Berkeley, CA 94710

CORRESPONDENCE Michel Gilliet: mgilliet{at}mdanderson.org

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- without inducing maturation or the production of IL-6 and TNF-. 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- 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.

© 2009 Ganguly et al.
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