Saturated and aromatic aldehydes originating from skin and cutaneous bacteria activate the Nrf2‐keap1 pathway in human keratinocytes

Abstract

Skin homeostasis is constantly challenged by environmental factors, affecting its delicate redox balance. The skin is also home to a wide variety of bacterial species, including Staphylococci. The cutaneous redox state is governed by the Nrf2-keap1 pathway, which is responsible for the induction of phase II cytoprotective enzymes, thus sustaining a healthy oxidative state. As part of normal metabolism, both bacteria and cutaneous tissue emit copious amounts of volatile organic compounds (VOCs),

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

“…Direct Nrf2 activation [ 50 ] occurs when an electrophilic entity enters or accumulates in the cytoplasm. Such molecules may be ROS, oxidative xenobiotics, nutrients, etc., or endogenous electrophiles deriving from cellular metabolism and lipid peroxidation processes occurring, for instance, in the skin and/or cutaneous bacteria [ 51 , 52 , 53 ]. The indirect activation mechanism includes intracellular production of endogenous ROS in low concentration in response to certain stress stimuli (e.g., UV irradiation, air pollutants, mosquito bites, etc.…”

“…It is highly striking that such a pivotal mechanism will have no endogenous triggers. We have very recently proposed [ 51 ] two possible skin-associated activators for this important pathway, lipid peroxidation end products and the cutaneous microbiome.…”

“…Thus, the ALEs produced during the peroxidation process may actually activate a negative feedback mechanism. Indeed, our recently published work [ 51 ] shows that the cutaneous ALEs nonanal, decanal and benzaldehyde, induced the Nrf2–Keap1 pathway in human keratinocytes while also granting protection against UVB-induced apoptosis. Therefore, it can be speculated that there is a feedback-based mechanism which relies on a moderate induction of lipid peroxidation processes by ROS originating from cutaneous exposures, leading to the accumulation of ALEs.…”

“…in the GI tract were able to induce the Nrf2–Keap1 pathway in epithelial cells via beneficial OS induction, or more accurately, by oxidative eustress induction [ 73 ]. We recently showed that a newly described cutaneous bacteria metabolite, 3-furaldehyde, induces the pathway in human keratinocytes [ 51 ], while also providing protection against UVB-induced apoptosis. We further suggest that microbial presence on the skin’s surface is sensed as a sort of moderate stress, which results, as in the case of other stressors, in endogenous production of electrophiles which in turn activate the protective Nrf2–Keap1 pathway.…”

Topical L‐thyroxine: The Cinderella among hormones waiting to dance on the floor of dermatological therapy?

“…For example, hyperbaric oxygen therapy (HBOT) shows a wide range of effects from clinical benefit to some patients to no improvements in others 185 . Nrf2 (the master transcription factor which regulates oxidative damage responses in human skin and HFs) 186‐188 that protects from excessive ROS as well as SDF‐1a levels is associated with clinically beneficial HBOT outcomes, suggesting that Nrf2 and SDF‐1 levels may serve as biomarkers for identifying those ulcer patients who may benefit from HBOT therapy 189 . Similar biomarkers may help to identify ulcer patients who promise optimal treatment outcomes after topical T4 therapy.…”