Redox regulation of cutaneous inflammasome by ozone exposure

Abstract

Several pollutants have been shown to affect skin physiology, among which ozone (O₃) is one of the most toxic. Prolonged exposure to O₃ leads to increased oxidative damage and cutaneous inflammation. The correlation between O₃ exposure and inflammatory cutaneous conditions (atopic dermatitis, psoriasis, acne and eczema) has been already suggested, although the mechanism involved is still unclear. In the last few decades, a new multiprotein complex, the inflammasome, has been discovered and linked to tissue inflammation, including inflammatory skin conditions. The inflammasome activates inflammatory responses and contributes to the maturation of cytokines such as interleukin 1β (IL-1β) and interleukin 18. This complex is also responsive to reactive oxygen species (ROS), which plays a role in triggering the activation of the complex. On this basis it is possible hypothesize that the activation of the inflammasome could be the link between the inflammatory skin conditions associated to O3 exposure. In the present work, the ability of O3 to induce inflammasome activation was determined in different skin models, ranging from 2D (human keratinocytes) to 3D models in vitro and ex vivo. Results clearly showed that O₃ exposure increased both transcript and protein levels of the main inflammasome complex, such as ASC and caspase-1. Furthermore, by using both immunofluorescence and an ASC oligomerization assay the formation of the complex was determined together with increased secreted levels of both IL-18 and IL-1β. Of note is that H2O2 and to a less extent 4HNE (both considered the main mediators of O3 interaction with cellular membranes) were also able to activate skin inflammasome while the use of catalase prevents the activation. This study demonstrated that O3 can activate cutaneous inflammasome in a redox dependent manner suggesting a possible role of this new pathway in pollution induced inflammatory skin conditions.