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

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

IL-36γ drives skin toxicity induced by EGFR/MEK inhibition and commensal Cutibacterium acnes

“…Similarly, doxycycline-inducible overexpression of wild-type KLF4 enhanced IL-36γ transcriptional activity, whereas a dominant-negative KLF4 mutant did not ( Figure 5B). This demon- exanthematous pustulosis (AGEP), and acrodermatitis continua Hallopeau (60,61). The data presented here provide substantial evidence that acneiform skin toxicity caused by EGFR/MEK inhibition should be added to the growing list of pustular skin diseases in which IL-36 likely plays a central pathogenic role.…”

A Comprehensive Review of HLA and Severe Cutaneous Adverse Drug Reactions: Implication for Clinical Pharmacogenomics and Precision Medicine

“…The recent studies about genetic predisposing identified mutation IL-36RN in AGEP patients [58]. These mutations lead to increase expression of various pro-inflammatory cytokines and chemokines such as IL-36 signaling, up-regulating IL-1, IL-6, CXCL 8/IL-8 production and neutrophil recruitment [54,59]. Etiology, pathology and treatments of SCARs have been extensively described as reviewed by other authors [60][61][62].…”

Cigarette Smoke Underlies the Pathogenesis of Palmoplantar Pustulosis via an IL-17A–Induced Production of IL-36γ in Tonsillar Epithelial Cells

“…Recent studies suggested that PPP, generalized pustular psoriasis, and acute generalized exanthematous pustulosis are commonly characterized by unique molecular alterations associated with IL-36einduced neutrophilic inflammation (Arakawa et al, 2018;Johnston et al, 2017;Liang et al, 2017;Meier-Schiesser et al, 2019). IL-36 is a collective name for three members of the IL-1 superfamily: IL-36a, IL-36b, and IL-36g (Sims and Smith, 2010;Towne and Sims, 2012).…”