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NETs generate structured antimicrobial peptide-nucleosome immune complexes with inter-DNA spacings optimal for TLR9 activation

Lee, E. Y. and Leforestier, A. and Di Domizio, J. and Curk, T. and Abbaspour, L. and Berezhnoy, N. and Fazli, H. and Nordenskiold, L. and Dobnikar, J. and Gilliet, M. and Wong, G. C. (2019) NETs generate structured antimicrobial peptide-nucleosome immune complexes with inter-DNA spacings optimal for TLR9 activation. Journal of Investigative Dermatology, 139 (5). S3. ISSN 0022-202X. https://resolver.caltech.edu/CaltechAUTHORS:20190423-154616074

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Abstract

The molecular pathogenesis of psoriasis is characterized in part by breakdown of immune tolerance to self-DNA. Recent work demonstrates that the human antimicrobial peptide (AMP) LL37 overexpressed in psoriasis organizes naked DNA into periodic nanocrystals to potently hyperactivate Toll-like receptor 9 (TLR9) in plasmacytoid dendritic cells (pDCs). Interestingly, a subset of self-DNA in psoriatic lesions remain bound to histones as histone-DNA nucleosome core particles (NCPs) released from neutrophil extracellular traps (NETs). At present, it is unknown how NET components like AMPs interact with NCPs, and whether AMP-NCP complexes form structures compatible with TLR9 activation in psoriasis. Here, we combine synchrotron X-ray scattering, cryo-electron microscopy, and computer simulations to demonstrate that under a broad range of conditions, NCPs stack into columns that present periodically arranged dsDNA ligands like threads on a screw, allowing for optimal interdigitation with clusters of TLR9. Remarkably, simulations and electron microscopy indicate that the superhelical pitch of DNA wrapped around the NCP column relaxes to a value that is well-matched with the steric size of TLR9, which predicts strong immune activation. Taken together, our results suggest that AMPs can remodel the structural organization of nucleosomes from NETs into potent amplifiers of inflammation. Preliminary immune activation experiments will be presented.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1016/j.jid.2019.03.089DOIArticle
ORCID:
AuthorORCID
Wong, G. C.0000-0003-0893-6383
Additional Information:© 2019 Published by Elsevier Inc. Available online 19 April 2019.
Issue or Number:5
Record Number:CaltechAUTHORS:20190423-154616074
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20190423-154616074
Official Citation:E.Y. Lee, A. Leforestier, J. Di Domizio, T. Curk, L. Abbaspour, N. Berezhnoy, H. Fazli, L. Nordenskiold, J. Dobnikar, M. Gilliet, G.C. Wong, 013 NETs generate structured antimicrobial peptide-nucleosome immune complexes with inter-DNA spacings optimal for TLR9 activation, Journal of Investigative Dermatology, Volume 139, Issue 5, Supplement, 2019, Page S3, ISSN 0022-202X, https://doi.org/10.1016/j.jid.2019.03.089. (http://www.sciencedirect.com/science/article/pii/S0022202X19302805)
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:94896
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:23 Apr 2019 23:12
Last Modified:07 Apr 2020 16:12

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