title: Potent NLRP3 Inflammasome Activation by the HIV Reverse Transcriptase Inhibitor Abacavir.
abstract: There is experimental and clinical evidence that some exanthematous allergic drug hypersensitivity reactions are mediated by drug-specific T cells. We hypothesized that the capacity of certain drugs to directly stimulate the innate immune system may contribute to generate drug-specific T cells. Here we analyzed whether abacavir, an HIV-1 reverse transcriptase inhibitor often inducing severe delayed-type drug hypersensitivity, can trigger innate immune activation that may contribute to its allergic potential. We show that abacavir fails to generate direct innate immune activation in human monocytes but potently triggers IL-1β release upon pro-inflammatory priming with phorbol ester or Toll-like receptor stimulation. IL-1β processing and secretion were sensitive to Caspase-1 inhibition, NLRP3 knockdown, and K+efflux inhibition and were not observed with other non-allergenic nucleoside reverse transcriptase inhibitors, identifying abacavir as a specific inflammasome activator. It further correlated with dose-dependent mitochondrial reactive oxygen species production and cytotoxicity, indicating that inflammasome activation resulted from mitochondrial damage. However, both NLRP3 depletion and inhibition of K+efflux mitigated abacavir-induced mitochondrial reactive oxygen species production and cytotoxicity, suggesting that these processes were secondary to NLRP3 activation. Instead, depletion of cardiolipin synthase 1 abolished abacavir-induced IL-1β secretion, suggesting that mitochondrial cardiolipin release may trigger abacavir-induced inflammasome activation. Our data identify abacavir as a novel inflammasome-stimulating drug allergen. They implicate a potential contribution of innate immune activation to medication-induced delayed-type hypersensitivity, which may stimulate new concepts for treatment and prevention of drug allergies.
authors.affiliation: From the Department of Dermatology, Venereology and Allergology, University Hospital Würzburg, 97080 Würzburg, Germany.
authors.forename: Atiye
authors.initials: A
authors.lastname: Toksoy
authors.affiliation: From the Department of Dermatology, Venereology and Allergology, University Hospital Würzburg, 97080 Würzburg, Germany.
authors.forename: Helga
authors.initials: H
authors.lastname: Sennefelder
authors.affiliation: From the Department of Dermatology, Venereology and Allergology, University Hospital Würzburg, 97080 Würzburg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Adam
authors.affiliation: From the Department of Dermatology, Venereology and Allergology, University Hospital Würzburg, 97080 Würzburg, Germany.
authors.forename: Sonja
authors.initials: S
authors.lastname: Hofmann
authors.affiliation: From the Department of Dermatology, Venereology and Allergology, University Hospital Würzburg, 97080 Würzburg, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Trautmann
authors.affiliation: From the Department of Dermatology, Venereology and Allergology, University Hospital Würzburg, 97080 Würzburg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Goebeler
authors.affiliation: From the Department of Dermatology, Venereology and Allergology, University Hospital Würzburg, 97080 Würzburg, Germany schmidt_M11@ukw.de.
authors.forename: Marc
authors.identifier: 0000-0002-8643-1615
authors.initials: M
authors.lastname: Schmidt
mesh_terms: D020170:Caspase 1 / Q000378:metabolism; D002478:Cells, Cultured; D015224:Dideoxynucleosides / Q000494:pharmacology*; D055785:Gene Knockdown Techniques; D006801:Humans; D007113:Immunity, Innate; D058847:Inflammasomes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000235:genetics / Q000276:immunology*; D011188:Potassium / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D000099227:Abacavir
chemical_list: D020170:Caspase 1; D015224:Dideoxynucleosides; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D011188:Potassium; D017382:Reactive Oxygen Species; D018894:Reverse Transcriptase Inhibitors; D000099227:Abacavir; C453881:NLRP3 protein, human
keywords: NLRP3; abacavir; allergy; caspase 1 (CASP1); drug hypersensitivity; inflammasome; innate immunity; interleukin 1 (IL-1)