The elucidation of mechanisms underlying severe cutaneous adverse drug reactions induced by neutrophils and the establishment of early diagnostic markers

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K16022
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53050:Dermatology-related
• Research Institution: University of Yamanashi
• Principal Investigator: Manao Kinoshita 山梨大学, 大学院総合研究部, 助教 (90813717)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: Stevens-Johnson症候群 / 中毒性表皮壊死症 / 好中球 / NETs / NETosis

Outline of Final Research Achievements

Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) are life-threatening mucocutaneous adverse drug reactions characterized by massive epidermal detachment. We found a mechanism by which neutrophils trigger inflammation during early phases of SJS/TEN. Skin-infiltrating neutrophils undergoing neutrophil extracellular traps (NETs) released LL-37, an antimicrobial peptide, which induced formyl peptide receptor 1 (FPR1) expression by keratinocytes. FPR1-expression rendered keratinocytes vulnerable to necroptosis. Necroptotic keratinocytes further released LL-37 to induce FPR1 expression on surrounding keratinocytes, which likely amplified the necroptotic response. This pathway may be leveraged to establish both early diagnostic markers and therapeutic targets.

Free Research Field

皮膚免疫

Academic Significance and Societal Importance of the Research Achievements

薬疹は内服薬や注射薬などの投薬により発症し、全身の皮膚粘膜に障害をきたす。特に重症薬疹である SJS/TEN は、全身の表皮壊死に加え多臓器障害を伴い、ときに致死的となる。仮に救命できても、失明など重篤な後遺症を残す患者は多い。薬剤による健康障害としては、重症薬疹が最多である (医薬品医療機器総合機構の集計)。
本来、治療目的で行われる投薬による医原性疾患であること、老若男女を問わず発症しうること、急激な転機で致死的になり得ることから、その病態解明と治療確立は切迫した課題である。