Abstract
The skin exerts several fundamental functions that are the first physical, chemical and immune barriers to the human body. Keratinocytes, the main cell type of the epidermis, provide mechanical defense, support skin integrity and actively endorse cutaneous immune responses. Not surprisingly, considering these crucial activities, alterations in keratinocyte functions are associated with different inflammatory skin diseases. Recent findings indicate that the skin should not only be regarded as a target for hormones but that it should also be considered as an endocrine peripheral organ that is directly involved in the synthesis and metabolism of these chemical messengers. Sex hormones have multiple effects on the skin, attributed to the binding with intracellular receptors expressed by different skin cell populations, including keratinocytes, that activate downstream signaling routes that modulate specific cellular functions and activities. This review is aimed at reorganizing the current knowledge on the role exerted by sex hormones on keratinocyte function in five different inflammatory skin diseases: Hidradenitis suppurativa; Acne vulgaris; Atopic dermatitis; progesterone hypersensitivity; psoriasis. The results of our work aim to provide a deeper insight into common cellular mechanisms and molecular effectors that might constitute putative targets to address for the development of specific therapeutic interventions.
Highlights
The skin possesses a well defined tripartite structure that, from the uttermost to the deepest layer, is provided by the epidermis, the dermis and the hypoderm
The physical and functional integrity of the skin is tightly linked to its specific structural partition into three layers [3,6]: the epidermis, the uppermost portion defined as a squamous stratified epithelium composed predominantly by keratinocytes and by dendritic cells (DCs); the dermis, the middle layer bearing a matrix of amorphous connective tissue and collagen, a nervous and vascular network, resident fibroblasts, mast cells and macrophages, and the epidermal appendages; the hypoderm, the deepest level represented by a subcutaneous vascularized tissue constituted by lobules of adipocytes separated by collagen fibres
Other relevant activities exerted by estrogens on human skin are: the regulation of the thickness of the skin and collagen deposition; the promotion of wound healing following the stimulation of dermal fibroblasts by estradiol [40]; the promotion of wound healing by E2 that induces the proliferation of basal epidermal keratinocytes via the Erk/Akt route [42]; the inactivation of estrogens by the sulfotransferase enzyme expressed in keratinocytes of the suprabasal layers, promoting keratinocyte differentiation and limiting cellular proliferation [43]
Summary
The skin possesses a well defined tripartite structure that, from the uttermost to the deepest layer, is provided by the epidermis, the dermis and the hypoderm. Over recent years, consistent evidence revealed that keratinocytes play supplementary roles that go beyond providing a sole protective barrier against external agents Upon stimulation, these cells are known to actively participate in the initiation and regulation of cutaneous inflammatory reactions by synthesizing, releasing and responding to different inflammatory, immunomodulatory and immunosuppressive mediators [3]. It is well established that keratinocytes are involved both in the production, activation and inactivation of hormones and in responding to circulating hormones that primarily influence differentiation and proliferation programs [1,3,4] In this intriguing context, a thorough characterization of the mechanisms underlying the complex interplay existing between defects in functional and immune properties of keratinocytes, cutaneous immune dysregulation and endocrine alterations should be further investigated since they may be closely associated with a continuously expanding spectrum of human immune-mediated skin diseases [5].
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