TLR7/8 agonists stimulate plasmacytoid dendritic cells to initiate a Th17-deviated acute contact dermatitis in humans

Publication date: Available online 19 September 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Natalie Garzorz-Stark, Felix Lauffer, Linda Krause, Jenny Thomas, Anne Atenhan, Regina Franz, Sophie Roenneberg, Alexander Boehner, Manja Jargosch, Richa Batra, Nikola S. Mueller, Stefan Haak, Christina Groß, Olaf Groß, Claudia Traidl-Hoffmann, Fabian J. Theis, Carsten B. Schmidt-Weber, Tilo Biedermann, Stefanie Eyerich, Kilian Eyerich
BackgroundA standardized human model to study early pathogenic events in psoriasis is missing. Activation of Toll-like receptor 7/8 by topical application of imiquimod is the most commonly used mouse model of psoriasis.ObjectiveTo investigate the potential of a human imiquimod patch test model to resemble human psoriasis.MethodsImiquimod (Aldara® 5% cream) was applied twice a week onto the back of volunteers (n=18) and the development of skin lesions was monitored over a time period of four weeks. Consecutive biopsies were taken for whole genome expression analysis, histology and T cell isolation. pDC were isolated from whole blood, stimulated with TLR7 agonist and analysed by extracellular flux analysis and real time PCR.ResultsWe demonstrate imiquimod induces a monomorphic and self-limited inflammatory response in healthy individuals as well as psoriasis or eczema patients, respectively. The clinical and histologic phenotype as well as transcriptome of imiquimod-induced inflammation in human skin resembles an acute contact dermatitis rather than psoriasis. Nevertheless, the imiquimod model mimics hallmarks of psoriasis. Namely, plasmacytoid dendritic cells (pDC) are primary sensors of imiquimod, responding with production of pro-inflammatory and Th17-skewing cytokines. This results in a Th17 immune response with IL-23 as a key driver. In a proof-of-concept setting, systemic treatment with ustekinumab diminished the imiquimod-induced inflammation.ConclusionIn humans, imiquimod induces contact dermatitis with the distinctive feature that pDC are the primary sensors, leading to an IL-23/Th17 deviation. Despite these shortcomings, the human imiquimod model might be useful to investigate early pathogenic events and prove molecular concepts in psoriasis.

Teaser

Stimulation of TLR7/8 in human skin induces an acute contact dermatitis with pDC as primary sensors and IL-23 as essential driver of the reaction, thus constituting a standardized, but limited model of human psoriasis.


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