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

By D. Ganguly, Georgios Chamilos, R. Lande, Josh Gregorio, S. Meller, V. Facchinetti, B. Homey, F. Barrat, T. Zal, M. Gilliet. Journal of Experimental Medicine, 2009

758 citations recorded by the source corpus.

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.

Subfields: Immunology

View Paper: https://www.semanticscholar.org/paper/eb9a1a914055005553c5f57e9f7b1c537f8b2b98

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In Immunology

1. Shizuo Akira
2. O. Takeuchi
3. G. Trinchieri
4. R. Medzhitov
5. B. Reizis
6. M. Kaplan
7. Taro Kawai
8. T. Mogensen

Citations in the corpus

• Plasmacytoid Dendritic Cells: Recent Progress and Open Questions (2011, background): “This and possibly other homologous proteins promote the aggregation of released cellular DNA and RNA into large complexes that efficiently activate pDCs (135, 136).”
• Type I interferon: friend or foe? (2010, background): “…complexes is not observed in psoriasis, the antimicrobial cationic peptide LL-37 accumulates in lesions where it binds to and transports self-DNA and RNA to the early endosomal compartment of pDC, thereby stimulating type I IFN production through TLR9 and TLR7, respectively (Ganguly et al., 2009).”
• Pattern recognition receptors and inflammation. (2010, background): “Similarly, the cationic antimicrobial peptide LL37 forms a complex with self-DNA or self-RNA, thereby facilitating endocytosis by pDCs and stimulating TLR-mediated IFN responses (Ganguly et al., 2009; Lande et al., 2007).”
• Psoriasis Pathogenesis and the Development of Novel, Targeted Immune Therapies (2017, neutral): “LL-37–mediated activation of DCs in the skin results in overproduction of type I interferons (IFN-a and IFN-b) by pDCs and increased amounts of TNF and IL-6 by mDCs.(31,32) A similar mechanism for pDC activation has also been described for human b-defensin (hBD) 2, hBD3, and lysozyme.”
• DAMPening Inflammation by Modulating TLR Signalling (2010, background): “TLR7, 8, and TLR9 expressed by pDCs respond to self-RNA and -DNA respectively when coupled with the endogenous antimicrobial peptide LL37 [91, 92].”
• Netting neutrophils induce endothelial damage, infiltrate tissues and expose immunostimulatory molecules in systemic lupus erythematosus (2011, background): “This occurs by binding the DNA to form condensed structures that are delivered to and retained within early endocytic compartments in pDCs to trigger TLR9 (23).”