Culprit Drugs Induce Specific IL-36 Overexpression in Acute Generalized Exanthematous Pustulosis

Meier-Schiesser, Barbara and Feldmeyer, Laurence and Jankovic, Dragana and Mellett, Mark and Satoh, Takashi K. and Yerly, Daniel and Navarini, Alexander and Abe, Riichiro and Yawalkar, Nikhil and Chung, Wen-Hung and French, Lars E. and Contassot, Emmanuel. (2019) Culprit Drugs Induce Specific IL-36 Overexpression in Acute Generalized Exanthematous Pustulosis. Journal of Investigative Dermatology, 139 (4). pp. 848-858.

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Acute generalized exanthematous pustulosis (AGEP) is a severe adverse cutaneous drug reaction. Although an involvement of drug-specific T cells has been reported, the physiopathology of AGEP and mechanism of neutrophilic skin inflammation remain incompletely understood. Recently, mutations in IL-36RN, the gene encoding the IL-36 receptor antagonist, have been reported to be more frequent in AGEP patients and pustular psoriasis. Here, we show that IL-36 cytokines, in particular IL-36γ, are highly expressed in lesional skin of AGEP patients, keratinocytes and macrophages being a major source of IL-36γ. Such an IL-36γ overexpression was not observed in patients with drug-induced maculopapular rash. In vitro, the causative drug specifically induced IL-36γ release either directly by the patient's peripheral blood monocytes or indirectly by keratinocytes in the presence of autologous peripheral blood mononuclear cells. Such culprit drug induction of IL-36γ secretion in vitro was specific for AGEP and involved toll-like receptor 4 sensing the drug/albumin complex as a danger signal. Our results suggest that IL-36γ secretion by monocytes/macrophages and keratinocytes in response to culprit drug exposure likely plays a key role in the pathogenesis of AGEP.
Faculties and Departments:03 Faculty of Medicine > Bereich Spezialfächer (Klinik) > Dermatologie USB > Dermatologie (Navarini)
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Spezialfächer (Klinik) > Dermatologie USB > Dermatologie (Navarini)
UniBasel Contributors:Navarini, Alexander
Item Type:Article, refereed
Article Subtype:Research Article
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:10 Jul 2020 14:09
Deposited On:10 Jul 2020 14:09

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