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

Nature Reviews Endocrinology volume 21, pages 495–509 (2025)Cite this article

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A Publisher Correction to this article was published on 02 May 2025

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Abstract

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.

Key points

  • The skin separates the internal milieu from the environment and is composed of the predominantly neuroectoderm-derived epidermis, an adjacent, predominantly mesoderm-derived dermis with hypodermis largely composed of fibroadipose tissue.

  • Skin is exposed to a variety of environmental signals, including solar radiation of different wavelengths, biological, physical and chemical insults, and pollutants.

  • Locally produced mediators, including classic pituitary and hypothalamic hormones, neuropeptides, cytokines and chemokines, biogenic amines, serotonin, melatonin, cannabinoids, steroids, and secosteroids, supported by a cutaneous neural network, regulate protective responses against environmental insults.

  • The skin neuro–immuno–endocrine system communicates with the local microbiome, neural, endocrine and immune systems through the production of soluble factors, priming circulating immune cells or neural transmission.

  • Environmental changes are detected and analysed locally and are transmitted to the central coordinating centres to regulate local and central homeostasis.

  • Selective activation of the skin neuro–immuno–endocrine system can have a role in protection against skin pathologies and in the prevention and treatment of systemic disorders, including autoimmune, neurodegenerative and cardiovascular disorders or carcinogenesis.

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Fig. 1: Skin homeostasis and allostasis are regulated by the local neuro–immuno–endocrine system in response to environmental factors.
Fig. 2: Cutaneous equivalents of the central HPA axis.
Fig. 3: Skin can regulate global body homeostasis and allostasis.

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Acknowledgements

The authors were supported by National Institutes of Health (NIH) grants 1R01AR073004, R01AR071189 and R21AI149267, VA Merit grant 2I01BX004293, and US Department of Defense grant #W81XWH2210689 and by the Intramural Research Program of the National Institute of Environmental Health Sciences, NIH Z01-ES-101586. We thank T.-K. Kim for his help in the preparation of the original versions of Figs. 1 and 2. Previous support by National Science Foundation grants IOS-0918934, IBN-9604364, 9896030 and 049087 and NIH grants RO1AR052190, 1R01AR056666, R21AR0665051 and AR-047079 to A.T.S., which contributed to the development of the presented concepts, is acknowledged.

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Authors and Affiliations

  1. Department of Medicine, Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, AL, USA

    Radomir M. Slominski

  2. Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL, USA

    Chander Raman & Andrzej T. Slominski

  3. Cell Biology Section, Immunity, Inflammation, and Disease Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA

    Anton M. Jetten

  4. Comprehensive Cancer Center, Cancer Chemoprevention Program, University of Alabama at Birmingham, Birmingham, AL, USA

    Andrzej T. Slominski

  5. Veteran Administration Medical Center, Birmingham, AL, USA

    Andrzej T. Slominski

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Slominski, R.M., Raman, C., Jetten, A.M. et al. Neuro–immuno–endocrinology of the skin: how environment regulates body homeostasis. Nat Rev Endocrinol 21, 495–509 (2025). https://doi.org/10.1038/s41574-025-01107-x

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