Autoimmune skin inflammation is dependent on plasmacytoid dendritic cell activation by nucleic acids via TLR7 and TLR9.
Recognition of endogenous DNA and RNA by cells expressing TLR7 and TLR9 is an important contributor to the pathogenesis of systemic lupus erythematosus and has been suggested to contribute to cutaneous lupus and to a group of related inflammatory skin diseases termed interface dermatitis. We have developed a mouse model of TLR7- and TLR9-dependent skin inflammation using tape stripping. In normal mice, this resulted in a rapid but transient inflammatory cell infiltration accompanied by induction of type I IFN production by plasmacytoid dendritic cells (PDCs) and release of extracellular traps and proinflammatory cytokines by neutrophils. These responses were strongly reduced in MyD88-deficient mice and in mice treated with a bifunctional inhibitor of TLR7 and TLR9. In contrast, in lupus-prone (NZBxNZW)F(1) mice, tape stripping induced the development of chronic lesions characterized by a persistent type I IFN gene signature and many clinical and histological features of cutaneous lupus. Depletion of PDCs before injury prevented the development of skin lesions, whereas treatment with a bifunctional TLR7/9 inhibitor before tape stripping or after the initial lesion was established led to a significant reduction of the disease. These data suggest that inhibitors of TLR7 and TLR9 signaling have potential therapeutic application for the treatment of interface dermatitis.
Dynavax Technologies Corporation, Berkeley, CA 94710, USA.
Cristiana
C
Guiducci
Claudio
C
Tripodo
Mei
M
Gong
Sabina
S
Sangaletti
Mario P
MP
Colombo
Robert L
RL
Coffman
Franck J
FJ
Barrat
D000818:Animals; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004247:DNA / Q000494:pharmacology; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000378:metabolism / Q000517:prevention & control; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000235:genetics; D009696:Nucleic Acids / Q000276:immunology*; D053633:Receptor, Interferon alpha-beta / Q000172:deficiency / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012867:Skin / Q000187:drug effects / Q000276:immunology / Q000293:injuries; D012871:Skin Diseases / Q000276:immunology* / Q000378:metabolism / Q000517:prevention & control; D051199:Toll-Like Receptor 7 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051217:Toll-Like Receptor 9 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D016207:Cytokines; C526793:IRS 954; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D009696:Nucleic Acids; C495370:Tlr9 protein, mouse; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; D053633:Receptor, Interferon alpha-beta; D004247:DNA