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  • br Psoriasis and permeability barrier br Conclusion The skin

    2018-11-15


    Psoriasis and permeability barrier
    Conclusion The skin is positioned at the interface of internal milieu and the external environment, and is equipped with physical, chemical, and immunological barriers against pathogen invasion. Perturbation in SC intercellular lipids following UV irradiation or physical injury to the skin promptly initiates the de novo synthesis of them, and DNA synthesis of epidermal keratinocytes, to restore the breached skin barrier and reestablish homeostasis as soon as possible. Antimicrobial peptides (AMPs) are also barrier components of the innate immunity defense during infection and injury. AMPs can recruit leukocytes to skin and stimulate them to release cytokines and chemokines. Psoriatic lesions are abundant in AMPs, including LL37, hBD-2, hBD-3, and S100A7/8/9. By contrast, AMPs are all downregulated in AD, being susceptible to infection. Although these two diseases share some features of epidermal abnormality, such as barrier defects, the difference of immunological polarity may stem from the innate immunity associated with AMPs in the epidermis. In conclusion, we hypothesize that psoriasis develops through the excessive response to a barrier defect that finally leads to Th17-skewed adaptive immunity (Figure 7). This involves: (1) barrier insults by trauma, infection, and others; (2) abnormal response of barrier recovery, which may be due to intercellular lipids deficiency, LCE gene defects, or abnormality in the intracellular signaling such as Stat3 activation; (3) resulting excessive AMPs, and abnormalities of epidermal differentiation and proliferation; and (4) all of which may lead to excessive, uncontrolled immune deviation toward Th17, for example. Thus, psoriasis pathogenesis represents a complicated vicious topirimate composed of a barrier defect, innate immune activation, and skewed adaptive immunity, each step of which may be associated with genetic predisposition.
    Acknowledgments This work was in part supported by Grants-in-Aids for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (21591436, 21591467, 21591656), by a fund subsidy of “Research on Measures for Intractable Diseases” from Ministry of Health, Labour, and Welfare of Japan (H23-028), and by grants from Center of Biomembrane Functions Controlling Biological Systems of the Kochi University Research Center Project.
    Introduction The brain serves as a receptor of environmental information from multiple sensory organs, and its massively interconnected neuronal network processes this information and transmits it to the systems of the whole body by secreting hormones and other messenger molecules to maintain homeostasis or generate appropriate responses. However, the digestive organs have an independent nervous system, which has been called the “second brain”. Here, I propose that the epidermis, which forms the interface between the body and the environment, can be considered a “third brain”. The basis for this idea is that epidermal keratinocytes express a variety of functional environmental sensors of temperature, mechanical stress, and chemical stimuli, as well as a series of neurotransmitters and their receptors that are known to play crucial roles in the brain. They can also secrete a range of hormones and neurotransmitters that influence whole-body state and emotions. Furthermore, cultured human keratinocytes can generate spatio-temporal electrochemical patterns similar to those seen in the brain. All the components of the hypothalamo–pituitary–adrenal (HPA) axis appear to be present in epidermal keratinocytes. Taking these results collectively, it is clear that the epidermis has many of the functional activities of the brain, in addition to sensory systems for multiple physical and chemical environmental factors. Here, I explore the hypothesis that the epidermis can be considered a “third brain”, by briefly reviewing the functions of epidermal keratinocytes and comparing them with those of the brain.