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Autoimmune skin inflammation is dependent on plasmacytoid dendritic cell activation by nucleic acids via TLR7 and TLR9.
- Source :
-
The Journal of experimental medicine [J Exp Med] 2010 Dec 20; Vol. 207 (13), pp. 2931-42. Date of Electronic Publication: 2010 Nov 29. - Publication Year :
- 2010
-
Abstract
- 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.
- Subjects :
- Animals
Cytokines genetics
Cytokines metabolism
DNA pharmacology
Dendritic Cells metabolism
Female
Flow Cytometry
Gene Expression
Lupus Erythematosus, Systemic metabolism
Lupus Erythematosus, Systemic prevention & control
Male
Mice
Mice, 129 Strain
Mice, Inbred C57BL
Mice, Inbred Strains
Mice, Knockout
Myeloid Differentiation Factor 88 deficiency
Myeloid Differentiation Factor 88 genetics
Receptor, Interferon alpha-beta deficiency
Receptor, Interferon alpha-beta genetics
Reverse Transcriptase Polymerase Chain Reaction
Skin drug effects
Skin immunology
Skin injuries
Skin Diseases metabolism
Skin Diseases prevention & control
Toll-Like Receptor 7 antagonists & inhibitors
Toll-Like Receptor 7 genetics
Toll-Like Receptor 9 antagonists & inhibitors
Toll-Like Receptor 9 deficiency
Toll-Like Receptor 9 genetics
Dendritic Cells immunology
Lupus Erythematosus, Systemic immunology
Nucleic Acids immunology
Skin Diseases immunology
Toll-Like Receptor 7 metabolism
Toll-Like Receptor 9 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1540-9538
- Volume :
- 207
- Issue :
- 13
- Database :
- MEDLINE
- Journal :
- The Journal of experimental medicine
- Publication Type :
- Academic Journal
- Accession number :
- 21115693
- Full Text :
- https://doi.org/10.1084/jem.20101048