Self-RNA-antimicrobial peptide complexes activate human dendritic cells through TLR7 and TLR8.
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-alpha without inducing maturation or the production of IL-6 and TNF-alpha. 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-alpha 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.
Ganguly
Dipyaman
D
Department of Immunology, The University of Texas M.D. Anderson Cancer Center, TX 77030, USA.
Chamilos
Georgios
G
Lande
Roberto
R
Gregorio
Josh
J
Meller
Stephan
S
Facchinetti
Valeria
V
Homey
Bernhard
B
Barrat
Franck J
FJ
Zal
Tomasz
T
Gilliet
Michel
M
D000595:Amino Acid Sequence; D023181:Antimicrobial Cationic Peptides / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D054804:Cathelicidins; D003713:Dendritic Cells / Q000276:immunology*; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D008156:Luciferases; D046911:Macromolecular Substances / Q000276:immunology / Q000378:metabolism*; D008969:Molecular Sequence Data; D011565:Psoriasis / Q000276:immunology*; D012313:RNA / Q000276:immunology / Q000378:metabolism*; D051199:Toll-Like Receptor 7 / Q000276:immunology / Q000378:metabolism*; D051200:Toll-Like Receptor 8 / Q000276:immunology / Q000378:metabolism*
D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins; D046911:Macromolecular Substances; C495348:TLR7 protein, human; C495349:TLR8 protein, human; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D012313:RNA; D008156:Luciferases
J Exp Med. 2000 May 15;191(10):1777-88
10811870
Eur J Gastroenterol Hepatol. 2006 Jun;18(6):615-21
16702850
Immunity. 2008 Mar;28(3):315-23
18342006
Proc Natl Acad Sci U S A. 2005 Dec 27;102(52):19057-62
16380428
Science. 2006 Mar 24;311(5768):1770-3
16497887
J Exp Med. 2009 Apr 13;206(4):743-50
19307328
Nat Immunol. 2006 Jan;7(1):49-56
16341217
Immunity. 2005 Aug;23(2):165-75
16111635
Nature. 2007 Oct 4;449(7162):564-9
17873860
J Biol Chem. 2004 Apr 23;279(17):17951-6
14963039
Mol Ther. 2007 Sep;15(9):1663-9
17579574
J Clin Invest. 2005 Feb;115(2):407-17
15668740
Eur J Immunol. 2001 Nov;31(11):3388-93
11745357
Autoimmunity. 2003 Dec;36(8):463-72
14984023
Annu Rev Immunol. 2002;20:709-60
11861616
J Exp Med. 2005 Jul 4;202(1):135-43
15998792
Nat Immunol. 2004 Dec;5(12):1219-26
15549123
Nature. 2000 Dec 7;408(6813):740-5
11130078
Nat Rev Immunol. 2008 Aug;8(8):594-606
18641647
Science. 2004 Mar 5;303(5663):1526-9
14976262
J Immunol. 1998 Aug 15;161(4):1947-53
9712065
Nat Med. 2007 Aug;13(8):975-80
17676051
J Invest Dermatol. 2008 Aug;128(8):1964-8
18323789
J Exp Med. 2009 Jan 16;206(1):249-58
19114666
Eur Respir J. 2007 Apr;29(4):624-32
17215317
Nature. 2001 Oct 18;413(6857):732-8
11607032
J Immunol. 2002 May 1;168(9):4531-7
11970999
J Exp Med. 2005 Oct 17;202(8):1131-9
16230478
J Clin Invest. 2007 Mar;117(3):803-11
17290304
Acta Otolaryngol. 2003 Jan;123(1):81-5
12625579
Immunity. 2006 Sep;25(3):417-28
16973389
J Exp Med. 2001 Sep 17;194(6):863-9
11561001
J Pathol. 2002 Nov;198(3):369-77
12375270
Cell. 2006 Feb 24;124(4):783-801
16497588
Proc Natl Acad Sci U S A. 2004 Apr 13;101(15):5598-603
15034168
Immunity. 2007 Nov;27(5):801-10
17997333
Nature. 2002 Apr 11;416(6881):603-7
11948342
Am J Respir Crit Care Med. 1999 Jul;160(1):283-90
10390413
Science. 2004 Mar 5;303(5663):1529-31
14976261
Eur J Immunol. 2007 Dec;37(12):3582-6
18034431
Arthritis Rheum. 2004 Jun;50(6):1861-72
15188363
J Exp Med. 2005 Nov 7;202(9):1171-7
16260486
Eur J Immunol. 2006 Dec;36(12):3256-67
17111347