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Toll-like receptor 7/8 agonists stimulate plasmacytoid dendritic cells to initiate T H 17-deviated acute contact dermatitis in human subjects.
- Source :
-
The Journal of allergy and clinical immunology [J Allergy Clin Immunol] 2018 Apr; Vol. 141 (4), pp. 1320-1333.e11. Date of Electronic Publication: 2017 Sep 19. - Publication Year :
- 2018
-
Abstract
- Background: A standardized human model to study early pathogenic events in patients with psoriasis is missing. Activation of Toll-like receptor 7/8 by means of topical application of imiquimod is the most commonly used mouse model of psoriasis.<br />Objective: We sought to investigate the potential of a human imiquimod patch test model to resemble human psoriasis.<br />Methods: Imiquimod (Aldara 5% cream; 3M Pharmaceuticals, St Paul, Minn) was applied twice a week to the backs of volunteers (n = 18), and development of skin lesions was monitored over a period of 4 weeks. Consecutive biopsy specimens were taken for whole-genome expression analysis, histology, and T-cell isolation. Plasmacytoid dendritic cells (pDCs) were isolated from whole blood, stimulated with Toll-like receptor 7 agonist, and analyzed by means of extracellular flux analysis and real-time PCR.<br />Results: We demonstrate that imiquimod induces a monomorphic and self-limited inflammatory response in healthy subjects, as well as patients with psoriasis or eczema. The clinical and histologic phenotype, as well as the transcriptome, of imiquimod-induced inflammation in human skin resembles acute contact dermatitis rather than psoriasis. Nevertheless, the imiquimod model mimics the hallmarks of psoriasis. In contrast to classical contact dermatitis, in which myeloid dendritic cells sense haptens, pDCs are primary sensors of imiquimod. They respond with production of proinflammatory and T <subscript>H</subscript> 17-skewing cytokines, resulting in a T <subscript>H</subscript> 17 immune response with IL-23 as a key driver. In a proof-of-concept setting systemic treatment with ustekinumab diminished imiquimod-induced inflammation.<br />Conclusion: In human subjects imiquimod induces contact dermatitis with the distinctive feature that pDCs are the primary sensors, leading to an IL-23/T <subscript>H</subscript> 17 deviation. Despite these shortcomings, the human imiquimod model might be useful to investigate early pathogenic events and prove molecular concepts in patients with psoriasis.<br /> (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Administration, Cutaneous
Adult
Aged
Biomarkers metabolism
Case-Control Studies
Dermatitis, Contact pathology
Female
Flow Cytometry
Humans
Imiquimod administration & dosage
Immunohistochemistry
Male
Middle Aged
Psoriasis pathology
Real-Time Polymerase Chain Reaction
Toll-Like Receptor 8 agonists
Dendritic Cells metabolism
Dermatitis, Contact metabolism
Imiquimod adverse effects
Models, Biological
Psoriasis metabolism
Th17 Cells metabolism
Toll-Like Receptor 7 agonists
Subjects
Details
- Language :
- English
- ISSN :
- 1097-6825
- Volume :
- 141
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- The Journal of allergy and clinical immunology
- Publication Type :
- Academic Journal
- Accession number :
- 28935206
- Full Text :
- https://doi.org/10.1016/j.jaci.2017.07.045