The Trinity of Skin: Skin Homeostasis as a Neuro-Endocrine-Immune Organ

Abstract

For a long time, skin was thought to be no more than the barrier of our body. However, in the last few decades, studies into the idea of skin as an independent functional organ have gradually deepened our understanding of skin and its functions. In this review, we gathered evidence that presented skin as a "trinity" of neuro-endocrine-immune function. From a neuro perspective, skin communicates through nerves and receptors, releasing neurotrophins and neuropeptides; from an endocrine perspective, skin is able to receive and secrete most hormones and has the cutaneous equivalent of the hypothalamic-pituitary-adrenal (HPA) axis; from an immune perspective, skin is protected not only by its physical barrier, but also immune cells and molecules, which can also cause inflammation. Together as an organ, skin works bidirectionally by operating peripheral neuro-endocrine-immune function and being regulated by the central nervous system, endocrine system and immune system at the same time, maintaining homeostasis. Additionally, to further explain the "trinity" of cutaneous neuro-endocrine-immune function and how it works in disease pathophysiology, a disease model of rosacea is presented.

Keywords: homeostasis; neuro–endocrine–immune; rosacea; skin.

Figure 1

Rosacea disease model of cutaneous neuro–endocrine–immune system. The TLRs represent the sentinel of cutaneous immune system. The CRH represents the action of cutaneous endocrine system. The TRPV/TRPA represents the sentinel of cutaneous nervous system. The parts belongs to cutaneous nervous, endocrine and immune system are colored in blue, red and yellow, respectively. The combination of disruption of the cutaneous neuro–endocrine–immune system results in the final clinical manifestation of rosacea. Abbreviations: CGRP: calcitonin gene-related protein; CRH: corticotropin releasing hormone; DAMPs: damage-associated molecular patterns; KLK5: kallikrein 5; SP: substance P; TLRs: Toll-like receptors; TRPV/TRPA: transient receptor potential vanilloid/transient receptor potential ankyrin; UV: ultraviolet; VIP: vasoactive intestinal peptide.

Figure 2

Skin as a “trinity” of a neuro–endocrine–immune organ. In this illustration, skin is divided into cutaneous nervous, endocrine and immune system. Cutaneous nervous system senses extrinsic stimuli via sensory nerves and receptors, communicates with CNS and provides NPs, NTs which can stimulate immune cells [23]. Cutaneous immune system is composed of innate immune cells, adaptive immune cells and KCs. It senses PAMPs and DAMPs through PRRs on KCs and innate immune cells [110], participates in inflammation and communicate with systemic immune system through cytokines, immune cell migrating and homing. Cutaneous endocrine system, especially the de novo hormone synthesis “plant”, KCs, is able to synthesize GCs [59] and vitamin D [61], regulate local and systemic homeostasis. Endocrine receptors*: including glucocorticoid receptors, mineralocorticoid receptor, thyroid hormone receptors, insulin receptors and insulin-like growth factor 1 (IGF-1) receptors, etc. Abbreviations: ACTH: adrenocorticotropic hormone; ARs: androgen receptors; CNS: central nervous system; DAMPs: damage-associated molecular patterns; DC: dendritic cell; GCs: glucocorticoids; KC: keratinocyte; LC: Langerhans cell; MC: mast cell; NPs: neuropeptides; NTs: neurotrophins; PAMPs: pathogen-associated molecular patterns; PRR: pattern-recognition receptors; SALT: skin-associated lymphoid tissue; SP: substance P, VD3: vitamin D3; 7-DHC: 7-dehydrocholesterol.