Abstract
BackgroundUrushiols are pro-electrophilic haptens that cause severe contact dermatitis mediated by CD8+ effector T-cells and downregulated by CD4+ T-cells. However, the molecular mechanism by which urushiols stimulate innate immunity in the initial stages of this allergic reaction is poorly understood. Here we explore the sub-cellular mechanisms by which urushiols initiate the allergic response.ResultsElectron microscopy observations of mouse ears exposed to litreol (3-n-pentadecyl-10-enyl-catechol]) showed keratinocytes containing swollen mitochondria with round electron-dense inclusion bodies in the matrix. Biochemical analyses of sub-mitochondrial fractions revealed an inhibitory effect of urushiols on electron flow through the mitochondrial respiratory chain, which requires both the aliphatic and catecholic moieties of these allergens. Moreover, urushiols extracted from poison ivy/oak (mixtures of 3-n-pentadecyl-8,11,13 enyl/3-n-heptadecyl-8,11 enyl catechol) exerted a higher inhibitory effect on mitochondrial respiration than did pentadecyl catechol or litreol, indicating that the higher number of unsaturations in the aliphatic chain, stronger the allergenicity of urushiols. Furthermore, the analysis of radioactive proteins isolated from mitochondria incubated with 3H-litreol, indicated that this urushiol was bound to cytochrome c1. According to the proximity of cytochromes c1 and b, functional evidence indicated the site of electron flow inhibition was within complex III, in between cytochromes bL (cyt b566) and bH (cyt b562).ConclusionOur data provide functional and molecular evidence indicating that the interruption of the mitochondrial electron transport chain constitutes an important mechanism by which urushiols initiates the allergic response. Thus, mitochondria may constitute a source of cellular targets for generating neoantigens involved in the T-cell mediated allergy induced by urushiols.
Highlights
Urushiols are pro-electrophilic haptens that cause severe contact dermatitis mediated by C D8+ effector T-cells and downregulated by CD4+ T-cells
To elucidate the mechanisms underlying this mitochondrial damage, we focused our study on the effect of urushiols at the level of the electron transport chain using mitochondria isolated from the rat liver, which is an extremely rich source of respiratory enzyme systems, cytochromes, and other compounds and could be analyzed with the biochemical methods used in the study [21]
Litreol is a noncompetitive inhibitor of complex III at the level of the cytochrome b c1 to define whether urushiols exerted an inhibitory action along the respiratory chain, we first studied the effect of urushiol on the respiration of rat liver mitochondria in a resting state
Summary
Urushiols are pro-electrophilic haptens that cause severe contact dermatitis mediated by C D8+ effector T-cells and downregulated by CD4+ T-cells. It was accepted that electrophilic haptens must first modify skin proteins by attacking free amino or sulfhydryl groups of self-antigens to induce an allergic reaction [6]. It was recently demonstrated [9] that unmodified urushiols from poison ivy/oak might be presented on CD1a molecules to human lymphocytes. Current evidence shows two potential nonexclusive mechanisms involved in urushiol-induced allergy: the first one is associated with the presentation of unmodified urushiols as foreign immunogenic antigens, and the second one involves the generation of neoantigens by covalent modification of self-proteins [9]. Since mice lack Cd1a because of a massive genetic deletion of group 2 of lipid-presenting molecules, except for Cd1d [10], they constitute an excellent experimental model for analyzing the role of neoantigens in allergies caused by urushiols
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