Neuro–immuno–endocrinology of the skin: how environment regulates body homeostasis

The skin, including the hypodermis, is the largest organ of the body. The epidermis, the uppermost layer, is in direct contact with the environment and is exposed to environmental stressors, including solar radiation and biological, chemical and physical factors. These environmental factors trigger local responses within the skin that modulate homeostasis on both the cutaneous and systemic levels. Using mediators in common with brain pathways, immune and neuroendocrine systems within the skin regulate these responses to activate various signal transduction pathways and influence the systemic endocrine and immune systems in a context-dependent manner. This skin neuro–immuno–endocrine system is compartmentalized through the formation of epidermal, dermal, hypodermal and adnexal regulatory units. These units can act separately or in concert to preserve skin integrity, allow for adaptation to a changing environment and prevent the development of pathological processes. Through activation of peripheral nerve endings, the release of neurotransmitters, hormones, neuropeptides, and cytokines and/or chemokines into the circulation, or by priming circulating and resident immune cells, this system affects central coordinating centres and global homeostasis, thus adjusting the body’s homeostasis and allostasis to optimally respond to the changing environment. The skin is not only a physical barrier between the body and the environment but also contains neural, immune and endocrine factors acting together to respond to external stimuli. This Review discusses the role of the skin as a neuro–immuno–endocrine organ and its influence on whole-body homeostasis and allostasis.