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

Meier-Schiesser, Barbara; Feldmeyer, Laurence; Jankovic, Dragana; Mellett, Mark; Satoh, Takashi K.; Yerly, Daniel; Navarini, Alexander; Abe, Riichiro; Yawalkar, Nikhil; Chung, Wen-Hung; French, Lars E. and Contassot, Emmanuel (2019): Culprit Drugs Induce Specific IL-36 Overexpression in Acute Generalized Exanthematous Pustulosis. In: Journal of Investigative Dermatology, Vol. 139, No. 4: pp. 848-858

Abstract

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-36 gamma, are highly expressed in lesional skin of AGEP patients, keratinocytes and macrophages being a major source of IL-36 gamma. Such an IL-36 gamma overexpression was not observed in patients with drug-induced maculopapular rash. In vitro, the causative drug specifically induced IL-36 gamma 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-36 gamma 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-36 gamma secretion by monocytes/ macrophages and keratinocytes in response to culprit drug exposure likely plays a key role in the pathogenesis of AGEP.

• Item Type: Journal article
• Faculties: Medicine
• Subjects: 600 Technology > 610 Medicine and health
• ISSN: 0022-202X
• Language: English