Research ArticleCUTANEOUS DRUG REACTIONS

Plasma exosomal miR-375-3p regulates mitochondria-dependent keratinocyte apoptosis by targeting XIAP in severe drug-induced skin reactions

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Science Translational Medicine  16 Dec 2020:
Vol. 12, Issue 574, eaaw6142
DOI: 10.1126/scitranslmed.aaw6142

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Excoriating exosomes

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe, potentially deadly drug-induced cutaneous reactions that result in skin death and detachment. Zhang et al. show that plasma exosomes from patients with SJS/TEN entered and promoted the apoptosis of primary human keratinocytes. They found that miR-375-3p was abundant in the patient-derived exosomes and correlated with clinical severity, and further showed that this microRNA induced keratinocyte cell death by targeting the apoptosis inhibitor XIAP. This work sheds light on the etiology of a serious skin condition and demonstrates how extracellular vesicles and their cargo can modify disease physiology.

Abstract

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe drug-induced cutaneous reactions characterized by keratinocyte apoptosis. Exosomes are nanometer-sized membranous vesicles in body fluids. They contain functional proteins, mRNAs, and miRNAs, which induce immune dysfunction and influence disease progression. However, their roles and mechanisms in SJS/TEN remain unknown. Our results demonstrate that exosomes isolated from the plasma of patients with SJS/TEN were 30 to 200 nm in diameter and expressed CD9, CD63, CD81, and TSG101 exosome marker proteins. miR-375-3p was markedly up-regulated in 35 patients with SJS/TEN and correlated with clinical severity. Plasma exosomes were internalized by human primary keratinocytes and promoted keratinocyte apoptosis in vitro. Furthermore, miR-375-3p overexpression promoted intrinsic (mitochondria-dependent) apoptosis of human primary keratinocytes via down-regulation of the X-linked inhibitor of apoptosis protein (XIAP), a key apoptosis regulator in primary human keratinocytes. In sum, our study indicates that the circulating exosomal miR-375-3p enters keratinocytes, down-regulates XIAP, and induces keratinocyte apoptosis in patients with SJS/TEN.

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