Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide.
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.
Lande
Roberto
R
Department of Immunology, M. D. Anderson Cancer Center, University of Texas, Houston, Texas 77030, USA.
Gregorio
Josh
J
Facchinetti
Valeria
V
Chatterjee
Bithi
B
Wang
Yi-Hong
YH
Homey
Bernhard
B
Cao
Wei
W
Wang
Yui-Hsi
YH
Su
Bing
B
Nestle
Frank O
FO
Zal
Tomasz
T
Mellman
Ira
I
Schröder
Jens-Michael
JM
Liu
Yong-Jun
YJ
Gilliet
Michel
M
D023181:Antimicrobial Cationic Peptides / Q000378:metabolism*; D001324:Autoantigens / Q000276:immunology / Q000378:metabolism*; D001327:Autoimmune Diseases / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D015551:Autoimmunity; D054804:Cathelicidins; D004247:DNA / Q000276:immunology / Q000378:metabolism*; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism*; D004705:Endocytosis; D011992:Endosomes / Q000276:immunology / Q000378:metabolism; D006801:Humans; D011565:Psoriasis / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051217:Toll-Like Receptor 9 / Q000276:immunology / Q000378:metabolism
D023181:Antimicrobial Cationic Peptides; D001324:Autoantigens; D054804:Cathelicidins; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9; D004247:DNA