Liquid-crystalline ordering of antimicrobial peptide-DNA complexes controls TLR9 activation.

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Schmidt, Nathan W 
Jin, Fan 
Lande, Roberto 
Curk, Tine 
Xian, Wujing 

Double-stranded DNA (dsDNA) can trigger the production of type I interferon (IFN) in plasmacytoid dendritic cells (pDCs) by binding to endosomal Toll-like receptor-9 (TLR9; refs 1-5). It is also known that the formation of DNA-antimicrobial peptide complexes can lead to autoimmune diseases via amplification of pDC activation. Here, by combining X-ray scattering, computer simulations, microscopy and measurements of pDC IFN production, we demonstrate that a broad range of antimicrobial peptides and other cationic molecules cause similar effects, and elucidate the criteria for amplification. TLR9 activation depends on both the inter-DNA spacing and the multiplicity of parallel DNA ligands in the self-assembled liquid-crystalline complex. Complexes with a grill-like arrangement of DNA at the optimum spacing can interlock with multiple TLR9 like a zipper, leading to multivalent electrostatic interactions that drastically amplify binding and thereby the immune response. Our results suggest that TLR9 activation and thus TLR9-mediated immune responses can be modulated deterministically.

Antimicrobial Cationic Peptides, Computer Simulation, CpG Islands, Crystallization, DNA, Dendritic Cells, Endosomes, Humans, Interferon Type I, Interferon-alpha, Liquid Crystals, Monte Carlo Method, Oligonucleotides, Scattering, Radiation, Static Electricity, Toll-Like Receptor 9, X-Rays, Cathelicidins
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Nat Mater
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Nature Publishing Group
Engineering and Physical Sciences Research Council (EP/I001352/1)
European Commission (234810)
European Research Council (227758)
This work is supported by NSF grants DMR1411329 and DMR1106106, EU grants ARG-ERC-COLSTRUCTION 227758 and ITN-COMPLOIDS 234810, by the Herchel Smith Fund, and by the Slovenian Research Agency through Grant P1-0055, and the Swiss National Science Foundation (FN 310030-144072). X-ray research was conducted at Stanford Synchrotron Radiation Lightsource, SLAC National Laboratory, supported by the US DOE Office of Basic Energy Sciences under Contract No. DE-AC02-76SF00515, the Advanced Light Source, supported by the US DOE Office of Basic Energy Sciences under Contract No. DE-AC02-05CH11231, and at the UCLA CNSI.