Even in monolayer cultured human

Even in monolayer-cultured human keratinocytes and rat skin organ culture, distinct spatio-temporal patterns were observed after physical or chemical stimulation. The plk1 inhibitor shows similar spatio-temporal dynamics after stimulation, and this phenomenon is strongly associated with information processing. It was recently suggested that information processing in response to mechanical stimuli might be carried out in the skin. Although the role of the electrochemical patterns observed in keratinocytes has not yet been clarified, it is plausible that they are associated with information processing in the plk1 inhibitor skin.

Signaling from keratinocytes to modulate whole body physiology and emotion
Immediately after barrier disruption, epidermal keratinocytes generate multiple cytokines, including interleukin-1 alpha and beta (IL-1α,β), IL-6, tumor necrosis factor alpha (TNFα), and interferon gamma (INFγ). For example, skin surface dryness induces IL-1α generation. UV-B-exposed keratinocytes secrete ATP, which induces IL-6 release. Thus, barrier abnormality or insult and UV-B irradiation may lead to release of multiple cytokines from epidermal keratinocytes. This is significant, because elevated serum cytokine levels are associated with impaired mental state, such as depression, in cancer patients Also, in patients with severe dermatitis, a large area of skin may be involved, and secretion of cytokines might be sufficient to influence mental state. This idea is consistent with a report that application of etanercept, a TNFα inhibitor, improved symptoms of depression and fatigue in psoriasis patients.
Epidermal keratinocytes produce not only cytokines, but also neurotransmitters and neuropeptides that could influence the peripheral nervous system or circulatory system. Moreover, all the components of the HPA axis appear to be present in epidermal keratinocytes. We previously demonstrated that keratinocytes generate and secrete oxytocin in response to stimulation with a stable ATP analog. Oxytocin is involved in behavior, memory and social bonding. Systemic oxytocin infusion reduced repetitive behavior in patients with autism and Asperger\’s syndrome. Therefore, oxytocin produced in epidermal keratinocytes could potentially influence mental state. Keratinocytes also generated neurotrophins like those originally found in the central nervous system.
Glucocorticoid also plays an important role in depression and post-traumatic stress disorder (PTSD), and might directly affect the hippocampus. We recently demonstrated that low environmental humidity induced generation and release of cortisol from epidermal keratinocytes of a skin equivalent model. We incubated the skin equivalent model under dry (relative humidity: <10%) and humid (relative humidity: approximately 100%) conditions for 48 hours and evaluated cortisol secretion and mRNA levels of cortisol-synthesizing enzyme (steroid 11β-hydroxylase; CYP11B1) and IL-1β. Cortisol secretion increased three-fold, and CYP11B1 and IL-1β mRNAs increased 38-fold and six-fold, respectively, in the dry condition versus the humid condition. Occlusion with a water-impermeable plastic membrane partially blocked the increases of cortisol secretion and CYP11B1 and IL-1β mRNA expression in the dry condition. Thus, environmental dryness might induce increased cortisol secretion in epidermis of diseased skin characterized by epidermal barrier dysfunction, potentially influencing mental state and systemic physiology.
Consequence of the hypothesis and discussion
There is extensive evidence that multiple sensory systems are functionally expressed in epidermal keratinocytes, together with a range of neurotransmitters and their receptors. Epidermal keratinocytes also secrete multiple bioactive molecules with the potential to influence whole-body physiology and emotional state. Thus, the epidermis appears to have the functional systems required for reception of environmental information from sensory organs, processing of that information, and transmission of it to the systems of the whole body. In other words, the epidermis, like the brain, has the capability to act as an interface between the body and the environment (Figure 1). Although much further research is needed to validate the idea that the epidermis serves as a “third brain”, this concept is an exciting one, opening up new vistas for the treatment of skin diseases and for our understanding of whole-body homeostasis.