Allergy-Inducing Chromium Compounds Trigger Potent Innate Immune Stimulation Via ROS-Dependent Inflammasome Activation

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• 作者：Christian Adam¹ ; Jonas Wohlfarth¹ ; Maike Hauß ; mann¹ ; Helga Sennefelder¹ ; Annette Rodin¹ ; Mareike Maler² ; Stefan F. Martin² ; Matthias Goebeler¹ ; Marc Schmidt¹ ; ^{schmidt_M11@ukw.de}
• 关键词：ATP ; adenosine triphosphate ; BMDC ; bone marrow-derived dendritic cell ; CrO42&ndash ; potassium chromate ; Cr2O72&ndash ; potassium dichromate ; Cr3+ ; chromium chloride ; chromium (III) ; trivalent chromium ; chromium (VI) ; hexavalent chromium ; DAMP ; damage-associated molecular pattern ; LDH ; lactate dehydrogenase ; LPS ; lipopolysaccharide ; NHEK ; normal human epidermal keratinocyte ; mROS ; mitochondrial reactive oxygen species ; TLR ; toll-like receptor ; TPA ; 12-O-tetradecanoylphorbol-13-acetate
• 刊名：Journal of Investigative Dermatology
• 出版年：2017
• 出版时间：February 2017
• 年：2017
• 卷：137
• 期：2
• 页码：367-376
• 全文大小：1787 K
• 卷排序：137

文摘

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.