Production of Superoxide Anions by Keratinocytes Initiates P. acnes-Induced Inflammation of the Skin

Abstract

Acne vulgaris is a chronic inflammatory disorder of the sebaceous follicles. Propionibacterium acnes (P. acnes), a gram-positive anareobic bacterium, plays a critical role in the development of these inflammatory lesions. This study aimed at determining whether reactive oxygen species (ROS) are produced by keratinocytes upon P. acnes infection, dissecting the mechanism of this production, and investigating how this phenomenon integrates in the general inflammatory response induced by P. acnes. In our hands, ROS, and especially superoxide anions (O₂^•−), were rapidly produced by keratinocytes upon stimulation by P. acnes surface proteins. In P. acnes-stimulated keratinocytes, O₂^•− was produced by NAD(P)H oxidase through activation of the scavenger receptor CD36. O₂^•− was dismuted by superoxide dismutase to form hydrogen peroxide which was further detoxified into water by the GSH/GPx system. In addition, P. acnes-induced O₂^•− abrogated P. acnes growth and was involved in keratinocyte lysis through the combination of O₂^•− with nitric oxide to form peroxynitrites. Finally, retinoic acid derivates, the most efficient anti-acneic drugs, prevent O₂^•− production, IL-8 release and keratinocyte apoptosis, suggesting the relevance of this pathway in humans. Acne vulgaris is a chronic inflammatory disorder of the sebaceous follicles. It is the most common skin disease, affecting up to 80% of individuals at some point between the ages of 11 and 30 years. Propionibacterium acnes (P. acnes) plays a role in the development of inflammatory acne lesions, but whether it causes inflammation by itself or through indirect mechanisms is not clear yet. Therefore, by exposing epidermal cells to P. acnes in vitro, we tested whether reactive oxygen species (ROS) production (oxidative burst) was involved in the inflammatory process. We found that one particular ROS, superoxide anion, was generated by epidermal cells following P. acnes stimulation. This phenomenon is associated with the production of a soluble pro inflammatory molecule, IL-8, and epidermal cell death. The abrogation of P. acnes-induced oxidative burst by the most commonly used and most efficient treatments of acne suggests that superoxide anions produced by epidermal cells are critical in the development of acne inflammatory lesions.