The Cutaneous Physiological Redox: Essential to Maintain but Difficult to Define.

Skin is a unique tissue, possessing extremely efficient protective and regulative mechanisms, similar only to the gut and lungs. These tissues serve as an interface with the environment and are exposed to stressors from both endogenous and exogenous sources. Interestingly, all these stressors lead downstream to a cellular production of reactive oxygen species (ROS) and other electrophiles, which, in turn could have deleterious outcomes for the living organism. Hence, such tissues should always maintain a "high-alert" condition in order to cope with these various insults. Nevertheless, a moderate production of ROS induced by stressors could actually be beneficial, although it is impossible to predict if and which exposure would lead to which outcome. Consequently, a parameter which would indicate the skin's readiness to cope with continuously fluctuating conditions is required. It has been proposed that the redox status may serve as a suitable indicator. In this opinion manuscript, we argue that the redox status is a vague parameter that is difficult to characterized and quantify due to its extremely dynamic nature. The common convention that the redox status is composed solely of the balance between oxidants and reductants (ROS and antioxidants) is also thought-provoking. Since this parameter in vivo behaves in a dynamic and complex manner, it better fits the description of a process, rather than an individual parameter. We suggest that the homeostatic modulation of the physiological redox (PR) should be in focus, rather than the redox status parameter itself. It is further suggested that low molecular weight antioxidants (LMWA) are, in fact, rather insignificant concerning the PR maintenance, and that the major contributors to this delicate modulation are regulative, protein-based systems such as the protective phase II antioxidant enzymes. Moreover, we show that skin microbiome and cutaneous advanced lipid peroxidation end-products (ALEs) take part in sustaining the cutaneous PR homoeostasis via activation of the Nrf2-Keap1 protective pathway.