Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide

Roberto Lande; Josh Gregorio; Valeria Facchinetti; Bithi Chatterjee; Yi Hong Wang; Bernhard Homey; Wei Cao; Yui Hsi Wang; Bing Su; Frank O. Nestle; Tomasz Zal; Ira Mellman; Jens Michael Schröder; Yong Jun Liu; Michel Gilliet

doi:10.1038/nature06116

Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide

Roberto Lande, Josh Gregorio, Valeria Facchinetti, Bithi Chatterjee, Yi Hong Wang, Bernhard Homey, Wei Cao, Yui Hsi Wang, Bing Su, Frank O. Nestle, Tomasz Zal, Ira Mellman, Jens Michael Schröder, Yong Jun Liu, Michel Gilliet

Immunology

Research output: Contribution to journal › Article › peer-review

1468 Scopus citations

Abstract

Plasmacytoid dendritic cells (pDCs) sense viral and microbial DNA through endosomal Toll-like receptors to produce type 1 interferons. pDCs do not normally respond to self-DNA, but this restriction seems to break down in human autoimmune disease by an as yet poorly understood mechanism. Here we identify the antimicrobial peptide LL37 (also known as CAMP) as the key factor that mediates pDC activation in psoriasis, a common autoimmune disease of the skin. LL37 converts inert self-DNA into a potent trigger of interferon production by binding the DNA to form aggregated and condensed structures that are delivered to and retained within early endocytic compartments in pDCs to trigger Toll-like receptor 9. Thus, our data uncover a fundamental role of an endogenous antimicrobial peptide in breaking innate tolerance to self-DNA and suggest that this pathway may drive autoimmunity in psoriasis.

Original language	English (US)
Pages (from-to)	564-569
Number of pages	6
Journal	Nature
Volume	449
Issue number	7162
DOIs	https://doi.org/10.1038/nature06116
State	Published - Oct 4 2007

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10.1038/nature06116

Cite this

@article{737006450b474c8b9b3f7b518e713876,

title = "Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide",

abstract = "Plasmacytoid dendritic cells (pDCs) sense viral and microbial DNA through endosomal Toll-like receptors to produce type 1 interferons. pDCs do not normally respond to self-DNA, but this restriction seems to break down in human autoimmune disease by an as yet poorly understood mechanism. Here we identify the antimicrobial peptide LL37 (also known as CAMP) as the key factor that mediates pDC activation in psoriasis, a common autoimmune disease of the skin. LL37 converts inert self-DNA into a potent trigger of interferon production by binding the DNA to form aggregated and condensed structures that are delivered to and retained within early endocytic compartments in pDCs to trigger Toll-like receptor 9. Thus, our data uncover a fundamental role of an endogenous antimicrobial peptide in breaking innate tolerance to self-DNA and suggest that this pathway may drive autoimmunity in psoriasis.",

author = "Roberto Lande and Josh Gregorio and Valeria Facchinetti and Bithi Chatterjee and Wang, {Yi Hong} and Bernhard Homey and Wei Cao and Wang, {Yui Hsi} and Bing Su and Nestle, {Frank O.} and Tomasz Zal and Ira Mellman and Schr{\"o}der, {Jens Michael} and Liu, {Yong Jun} and Michel Gilliet",

note = "Funding Information: Acknowledgements We thank G. Lizee for critical reading of the manuscript; E. Wieder and K. Ramirez from the Flow Cytometry Core Facility for performing cell sorting; J. Wygant from the Monoclonal Antibodies Core Facility for generating the anti-LL37 monoclonal antibody; J. Bartels for ESI-MS analyses; and G. Reyes for technical assistance. This work was funded by a grant from the M. D. Anderson Cancer Foundation to M.G. Part of this work was supported by grants from the {\textquoteleft}Deutsche Forschungsgemeinschaft{\textquoteright} to J.-M.S. and to B.H.",

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doi = "10.1038/nature06116",

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T1 - Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide

AU - Lande, Roberto

AU - Gregorio, Josh

AU - Facchinetti, Valeria

AU - Chatterjee, Bithi

AU - Wang, Yi Hong

AU - Homey, Bernhard

AU - Cao, Wei

AU - Wang, Yui Hsi

AU - Su, Bing

AU - Nestle, Frank O.

AU - Zal, Tomasz

AU - Mellman, Ira

AU - Schröder, Jens Michael

AU - Liu, Yong Jun

AU - Gilliet, Michel

N1 - Funding Information: Acknowledgements We thank G. Lizee for critical reading of the manuscript; E. Wieder and K. Ramirez from the Flow Cytometry Core Facility for performing cell sorting; J. Wygant from the Monoclonal Antibodies Core Facility for generating the anti-LL37 monoclonal antibody; J. Bartels for ESI-MS analyses; and G. Reyes for technical assistance. This work was funded by a grant from the M. D. Anderson Cancer Foundation to M.G. Part of this work was supported by grants from the ‘Deutsche Forschungsgemeinschaft’ to J.-M.S. and to B.H.

PY - 2007/10/4

Y1 - 2007/10/4

N2 - Plasmacytoid dendritic cells (pDCs) sense viral and microbial DNA through endosomal Toll-like receptors to produce type 1 interferons. pDCs do not normally respond to self-DNA, but this restriction seems to break down in human autoimmune disease by an as yet poorly understood mechanism. Here we identify the antimicrobial peptide LL37 (also known as CAMP) as the key factor that mediates pDC activation in psoriasis, a common autoimmune disease of the skin. LL37 converts inert self-DNA into a potent trigger of interferon production by binding the DNA to form aggregated and condensed structures that are delivered to and retained within early endocytic compartments in pDCs to trigger Toll-like receptor 9. Thus, our data uncover a fundamental role of an endogenous antimicrobial peptide in breaking innate tolerance to self-DNA and suggest that this pathway may drive autoimmunity in psoriasis.

AB - Plasmacytoid dendritic cells (pDCs) sense viral and microbial DNA through endosomal Toll-like receptors to produce type 1 interferons. pDCs do not normally respond to self-DNA, but this restriction seems to break down in human autoimmune disease by an as yet poorly understood mechanism. Here we identify the antimicrobial peptide LL37 (also known as CAMP) as the key factor that mediates pDC activation in psoriasis, a common autoimmune disease of the skin. LL37 converts inert self-DNA into a potent trigger of interferon production by binding the DNA to form aggregated and condensed structures that are delivered to and retained within early endocytic compartments in pDCs to trigger Toll-like receptor 9. Thus, our data uncover a fundamental role of an endogenous antimicrobial peptide in breaking innate tolerance to self-DNA and suggest that this pathway may drive autoimmunity in psoriasis.

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Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide

Abstract

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Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide

Abstract

ASJC Scopus subject areas

MD Anderson CCSG core facilities

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Fingerprint

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Monoclonal Antibody Facility (MAF)

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