title: Allergy-Inducing Chromium Compounds Trigger Potent Innate Immune Stimulation Via ROS-Dependent Inflammasome Activation.
abstract: Chromium allergy is a common occupational skin disease mediated by chromium (VI)-specific T cells that induce delayed-type hypersensitivity in sensitized individuals. Additionally, chromium (VI) can act as an irritant. Both responses critically require innate immune activation, but if and how chromium (VI) elicits this signal is currently unclear. Using human monocytes, primary human keratinocytes, and murine dendritic cells we show that chromium (VI) compounds fail to trigger direct proinflammatory activation but potently induce processing and secretion of IL-1β. IL-1β release required priming by phorbol-ester or toll-like receptor stimulation and was prevented by inhibition of K+efflux, NLRP3 depletion or caspase-1 inhibition, identifying chromium (VI) as a hapten activator of the NLRP3 inflammasome. Inflammasome activation was initiated by mitochondrial reactive oxygen species production triggered by chromium (VI), as indicated by sensitivity to treatment with the ROS scavenger N-acetyl cysteine and a coinciding failure of K+efflux, caspase-1, or NLRP3 inhibition to prevent mitochondrial reactive oxygen species accumulation. IL-1β release further correlated with cytotoxicity that was secondary to reactive oxygen species, K+efflux, and NLRP3 activation. Trivalent chromium was unable to induce mitochondrial reactive oxygen species production, inflammasome activation, and cytotoxicity, suggesting that oxidation state-specific differences in mitochondrial reactivity may determine inflammasome activation and allergic/irritant capacity of different chromium compounds.
authors.affiliation: Department of Dermatology, University Hospital Würzburg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Adam
authors.affiliation: Department of Dermatology, University Hospital Würzburg, Germany.
authors.forename: Jonas
authors.initials: J
authors.lastname: Wohlfarth
authors.affiliation: Department of Dermatology, University Hospital Würzburg, Germany.
authors.forename: Maike
authors.initials: M
authors.lastname: Haußmann
authors.affiliation: Department of Dermatology, University Hospital Würzburg, Germany.
authors.forename: Helga
authors.initials: H
authors.lastname: Sennefelder
authors.affiliation: Department of Dermatology, University Hospital Würzburg, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Rodin
authors.affiliation: Department of Dermatology, Allergy Research Group, Medical Centre-University of Freiburg, Germany.
authors.forename: Mareike
authors.initials: M
authors.lastname: Maler
authors.affiliation: Department of Dermatology, Allergy Research Group, Medical Centre-University of Freiburg, Germany.
authors.forename: Stefan F
authors.initials: SF
authors.lastname: Martin
authors.affiliation: Department of Dermatology, University Hospital Würzburg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Goebeler
authors.affiliation: Department of Dermatology, University Hospital Würzburg, Germany. Electronic address: schmidt_M11@ukw.de.
authors.forename: Marc
authors.initials: M
authors.lastname: Schmidt
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D017608:Chromium Compounds / Q000633:toxicity*; D006967:Hypersensitivity / Q000209:etiology* / Q000276:immunology; D007113:Immunity, Innate / Q000187:drug effects*; D053583:Interleukin-1beta / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D017608:Chromium Compounds; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D017382:Reactive Oxygen Species; D000255:Adenosine Triphosphate