Skin sensitization to fragrance hydroperoxides: interplay between dendritic cells, keratinocytes and free radicals. (30th December 2020)

• Record Type: Journal Article
• Authors: Lichter, J.; Silva e Sousa, M.; Peter, N.; Sahli, F.; Vileno, B.; Kuresepi, S.; Gourlaouen, C.; Giménez‐Arnau, E.; Blömeke, B.
• Is Part Of: British journal of dermatology. Volume 184:Number 6(2021)
• Page Start: 1143
• Page End: 1152
• Publication Date: 2020-12-30
• Subjects: Dermatology -- Periodicals; Skin -- Diseases -- Periodicals; 616.5
• DOI: 10.1111/bjd.19685
• Languages: English
• ISSNs: 0007-0963

Abstract

Summary: Background: Skin sensitization to hydroperoxides (R‐OOHs) of the commonly used fragrance terpenes limonene, linalool and citronellol is frequently reported. R‐OOHs are believed to initiate the process leading to sensitization and allergic contact dermatitis through mechanisms involving radical intermediates. Thus, radical intermediates, keratinocytes and dendritic cells (DCs) may act in concert to initiate the process. Objectives: To evaluate individual DC activation profiles by R‐OOHs in the context of keratinocytes with regard to frequency, specificity and magnitude of upregulation. Methods: We used 2D and 3D cocultures with keratinocytes/reconstructed human epidermis (RHE) and DCs to evaluate cell surface levels of the costimulatory molecules CD86, CD80 and the adhesion molecule CD54 on cocultured DCs. Analysis of radical formation from limonene hydroperoxides in RHE was performed using electron paramagnetic resonance combined with the spin trapping technique. Results: R‐OOHs induce donor‐dependent DC activation. Major differences were found between the limonene‐OOHs. Limonene‐1‐OOH was stronger with respect to both frequency and magnitude of response. Using a 3D coculture model, no DC activation was detected after topical application of 0·2% limonene‐OOHs (20 µg cm −2 ), while 1·2% limonene‐1‐OOH or 2% limonene‐2‐OOH induced DC activation. Furthermore, we demonstrated differences in the carbon and oxygen radicals formed from the limonene‐OOHs using RHE, mimicking what may happen in vivo . Conclusions: We report clear individual differences in DC maturation induced by the most important hydroperoxides. Response rates and magnitude of response both indicate that very small structural alterations in the hydroperoxides are translated into specific DC responses. In addition, we provide more insight into the amounts of hydroperoxides that can activate DCs and induce sensitization. Abstract : What is already known about this topic? Allylic hydroperoxides of commonly used fragrance terpenes are important contact allergens. Hydroperoxides have the potential to form free radicals. What does this study add? This study describes dendritic cell (DC) activation in the presence of keratinocytes induced by limonene, linalool and citronellol hydroperoxides. For limonene‐1 hydroperoxide, donor variations in keratinocytes were even more pronounced than variations arising from monocyte‐derived DC donors. We report the amounts of limonene‐1 hydroperoxide and limonene‐2 hydroperoxide required to induce DC activation. Radical intermediates derived from limonene hydroperoxides are formed in situ in a reconstructed human epidermis model and computational calculations confirm a preferential radical degradation pathway for limonene‐1 hydroperoxides. What is the translational message? This study provides new insights into interindividual differences in DC response to sensitizing hydroperoxides and information regarding the amounts required for induction of sensitization to limonene hydroperoxides. Linked Comment: Pilkington. Br J Dermatol 2021; 184 :1000–1001 .