Current Issue
Spring/Summer 2025, Vol. 32 No. 1
Hong Kong J. Dermatol. Venereol. (2025) 32, 71-75
Commentary
The evolving role of the skin immune system: from development to disease prevention
Introduction
As dermatologists, we are continually amazed by new discoveries in skin biology. The skin immune system is at the forefront of many such findings, with recent studies revealing how macrophages aid blood vessel and nerve development in fetal skin, and postnatally reduce skin damage, and support the microbiome. Remarkably, the skin can even produce its own antibodies. These findings offer exciting therapeutic novelty, from better characterisation of skin disease pathobiology, to improved sunburn treatments, to treating skin and systemic infections, and to future vaccination strategies.
The traditional role of skin macrophages
Adult human skin covers approximately 25 m² and contains around 35 billion cells. Although most of these cells are keratinocytes, another key cell among 40 or so different cell populations in skin is the macrophage. Macrophages are essential immune cells, playing a central role in maintaining health and influencing disease. First identified over 140 years ago by zoologist Élie Metchnikoff (Ilia Mechnikov), our comprehension of their functions has expanded enormously. These versatile cells are recognised as key players in pathogen detection, phagocytosis, and destruction, while also contributing to both innate and adaptive immunity, tissue repair, and regeneration. Additionally, macrophages present antigens to T cells, orchestrating inflammatory responses in the skin and other tissues.
Macrophages in skin development
Despite our growing understanding, the full spectrum of macrophage functions remains far from fully explored. A pioneering study published in Nature by Gopee et al,1 from the Haniffa lab (Newcastle/Cambridge), has unveiled an unexpected new dimension to macrophages' role-one that extends beyond immune defence into the realm of human skin development. These findings redefine the traditional view of macrophages, demonstrating their involvement in critical developmental processes such as blood vessel formation, fibroblast regulation, scarless wound healing, and neural patterning. This discovery challenges conventional wisdom, suggesting that macrophages are integral not only to immune surveillance but also to tissue morphogenesis.
Research methodology and key findings
To uncover these insights, the research team constructed a comprehensive multi-omics reference atlas of prenatal skin, integrating single-cell RNA sequencing with spatial transcriptomics. They also employed skin organoids derived from human embryonic stem cells and inducible pluripotent stem cells as a comparative model. Notably, these organoids lack immune cells, enabling researchers to contrast fetal skin environments with and without macrophages. This approach highlighted macrophages' unique contributions to fetal skin development in ways not previously appreciated.
Macrophages infiltrate fetal skin as early as six weeks post-conception, expressing pro-inflammatory genes. However, genes linked to Major Histocompatibility Complex class II antigen presentation remain inactive until 11 weeks, suggesting a distinct early phase where macrophages predominantly interact with non-immune cells. Spatial transcriptomics further delineated specialised microenvironments within fetal skin, each with unique immune cell compositions. Macrophages were found in close association with endothelial and neural cells, actively shaping vascular development through blood vessel remodelling and contributing to the organisation of the peripheral nervous system.
Scarless wound healing and macrophages
One of the most striking aspects of human fetal skin is its ability to heal wounds without scarring - an ability lost after approximately 24 weeks of gestation. Macrophages also appear to be key mediators of this phenomenon. A specific macrophage subset (LYVE1+) interacts with fibroblasts expressing WNT2+, modulating the inflammatory milieu by suppressing interleukin-6 and pro-fibrotic signalling pathways. This interaction creates an environment conducive to scarless tissue repair, in stark contrast to the fibrotic healing observed later in gestation and in postnatal skin.
Implications for dermatology and future research
Reflecting on these discoveries, one can only wonder how Élie Metchnikoff - who shared the 1908 Nobel Prize in Physiology or Medicine with Paul Ehrlich for his work on phagocytosis - would have reacted to such revelations about macrophages' unexpected roles in skin development. This study not only enriches our grasp of skin immunobiology but also opens exciting possibilities for therapeutic interventions. Whether in wound healing, regenerative medicine, or novel dermatological therapies, macrophages continue to reveal new secrets, reinforcing their status as some of the most adaptable and influential cells in human biology.
Macrophages, vitamin D, and sunburn injury response
Further underscoring the macrophage's considerable functional diversity, is a re-awakening of its role in skin injury response, notably in appreciating how vitamin D can modify skin macrophage biology to reduce tissue damage, for example in acute sunburn. Sunburn represents a complex inflammatory response in the body. The immune system mobilises neutrophils and macrophages to the damaged skin, releasing pro-inflammatory mediators such as tumour necrosis factor alpha.2 These macrophages further differentiate into inflammatory types that produce inducible nitric oxide synthase, intensifying inflammation and exacerbating tissue injury and giving rise to the sore irritated skin we recognise as sunburn.2
Potential therapeutic role of vitamin D
Most dermatologists would ponder treatment of severe cases of sunburn with topical or systemic corticosteroids. However, research suggests that taking a single oral dose of 100,000 to 200,000 IU of vitamin D3 (where 1,000 IU equals 25 μg) within hours of developing sunburn can significantly reduce inflammation,3 with the skin regaining its normal appearances by the following day. A large oral dose of vitamin D3 rapidly increases circulating levels of the inactive form, which accumulates in sunburned skin. Here, keratinocytes and macrophages convert it into its active form. Once activated, vitamin D3 interacts with UV-induced endogenous retinoids to drive the differentiation of anti-inflammatory ‘pro-resolution' macrophages. These cells express arginase-1 and autophagy markers, effectively calming the inflammatory response.4
Clinical considerations
Clinical data remain limited, although a double-blind, placebo-controlled study involving 20 participants found that administering a single dose of 50,000 to 200,000 IU of vitamin D3 one hour after exposure to erythemogenic UVB significantly reduced redness, histological skin damage, and inflammatory markers.5 Importantly, no adverse effects, including changes in serum calcium or phosphate levels, were observed: the kidneys naturally regulate these levels, preventing toxicity. However, the pharmacokinetics of high-dose vitamin D3 are complex, and the optimal dosing strategy for immune modulation is still under investigation. Could pre-emptive vitamin D3 supplementation provide similar benefits before sun exposure? The answer is unclear, though its effects seem most potent when administered post-injury. While single high-dose vitamin D3 is not yet a formally recommended treatment for sunburn, anecdotal and off-label use is increasing, although further large-scale studies are needed before it can be routinely integrated into clinical practice.
Potential new medical applications for single high dose vitamin D
For sunburn relief, a practical approach could involve taking a single 100,000 IU oral dose within 1 to 12 hours of overexposure. Most over-the-counter vitamin D3 supplements contain 1,000-10,000 IU per tablet (though higher-dose 50,000 IU tablets exist), requiring multiple tablets to reach the effective dose. While this may seem substantial, research supports its safety. The potential benefits of high-dose vitamin D3 extend beyond sunburn. Emerging research suggests its efficacy in other dermatological conditions, such as reducing radiation-induced dermatitis in breast cancer patients,6 alleviating acute radiation recall dermatitis following chemotherapy,7 and mitigating toxic erythema caused by chemotherapy.8
With mounting evidence for vitamin D3 as a tool for managing acute skin inflammation, its inclusion in sunburn care warrants consideration. Indeed, many dermatologists may now start to pack vitamin D3 tablets alongside topical sunscreen products when travelling to sunny destinations.
Langerhans cells and skin immunity
Aside from macrophages, another key antigen presenting cell in skin is the Langerhans cell. Typically regarded as a cell which uptakes antigen, processes it and then journeys from epidermis to lymph node to evoke tolerance or a cellular or antibody response, Langerhans cells have recently been shown to have other roles. Notably, Langerhans cells have a separate function in regulating the skin microbiome which involves generation of a semi-autonomous immune system in skin the controls the biomass of the microbiome, partly by making antibodies in skin (i.e. without involving the lymph nodes).
The skin microbiome: a complex and vital ecosystem
The outermost layer of skin is home to roughly 70 billion microbes, which play a vital role in regulating skin physiology and immunity. Despite advances in dermatological research, the intricate relationship between host and microbiota remains an area of ongoing exploration. However, two recent studies published in Nature have provided new insights into this dynamic, revealing that the skin can independently generate its own antibodies.9,10 These findings redefine the role of humoral immunity in maintaining skin homeostasis and combating infections.
Rethinking the immune balance in skin homeostasis
For a stable host-microbiota relationship, a non-inflammatory environment is essential, traditionally attributed to a balance of T-cell responses. While the presence of B cells and plasma cells in the skin has been well-documented, their role was largely thought to be infection-specific rather than homeostatic. Conventional understanding suggests that when the skin encounters new commensal microbes, Langerhans cells uptake antigens and transport them to lymph nodes, where germinal centre reactions generate an IgG antibody response.
Revising thoughts on localised humoral immunity in skin
However, research by Gribonika et al9 challenges this model, demonstrating (in mice) that Langerhans cells not only ferry antigens to lymph nodes but also facilitate the formation of tertiary lymphoid structures directly within the skin. These localised structures sustain IgG production independently of the lymph nodes, enabling continuous immune surveillance and regulation of microbiota biomass. Moreover, these antibodies provide dual protection - managing microbial homeostasis and defending against both local and systemic infections by the same organisms.
The role of CXCL13 in tertiary lymphoid structures
The study also identified CXCL13 as a key chemokine involved in recruiting B and T cells to tertiary lymphoid structures, which form around hair follicles through high endothelial venules.9 Intriguingly, this pathway operates independently of lymphotoxin-β receptor signalling, previously considered essential for tertiary lymphoid structure development.
Harnessing skin immunity for therapeutic benefit
Gribonika et al9 focused on Staphylococcus epidermidis as a model to explore the skin's humoral response mechanisms. Complementary research by Bousbaine et al10 examined how these immune mechanisms could be harnessed for therapeutic benefit. Their study (also in mice) revealed that S. epidermidis elicits a potent, durable, and specific antibody response even under normal colonisation conditions.
The potential for topical vaccination
A key cell surface antigen in S. epidermidis, accumulation-associated protein (Aap), was identified as a primary target for this response.10 By replacing part of Aap with a tetanus toxin fragment, the researchers induced a strong neutralising antibody response that successfully protected mice from a lethal tetanus challenge. Further experiments demonstrated that this antibody response extended beyond the skin to nasal and pulmonary mucosae, suggesting the feasibility of developing non-invasive topical vaccines.
A semi-autonomous immune system in the skin
These findings collectively propose that the skin possesses a semi-autonomous immune system capable of mounting pre-emptive responses to colonising microbes. This system involves active antigen sampling between epithelial cells and microbial niches, functioning as a natural form of vaccination against commensals residing in the skin barrier. Furthermore, regulatory T cells appear to play a critical role in this process, with evidence indicating their transformation into T follicular helper cells within tertiary lymphoid structures.
Challenges and future clinical applications
Looking toward clinical translation, the goal is to leverage the immune response to S. epidermidis for therapeutic applications, the concept being to deliver vaccines via topical creams, ointments, or nasal sprays as a promising alternative to traditional immunisation methods. However, humans naturally exhibit higher baseline antibody levels against S. epidermidis compared to mice, raising questions about the direct applicability of murine findings to human physiology. If these mechanisms are validated in human studies, rigorous safety and efficacy trials will be the next step, potentially ushering in a new era of alternative or complementary vaccination strategies.
Implications for dermatology practice
Collectively, these studies reveal exciting new basic and translational knowledge on the protean role of macrophages and Langerhans cells in human skin, findings that are likely to have very real relevance to our practice as dermatologists, both now and over the next few years, particularly in modulating our skin microbiome, the prevention and treatment of infection, and approaches to vaccination. Like an antigen presenting cell, there is certainly a lot for us to ingest and process. Our skin, and its immune network, is indeed truly fascinating.
Acknowledgements
John McGrath is Editor-in-Chief of the British Journal of Dermatology. This commentary was based on data assembled for editorials published in the British Journal of Dermatology in 2025.11-13 The assistance of Prof Kurt Lu (Chicago, USA) and Prof Kenji Kabashima (Kyoto, Japan) is gratefully acknowledged.
References
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2. Clydesdale GJ, Dandie GW, Muller HK. Ultraviolet light induced injury: immunological and inflammatory effects. Immunol Cell Biol 2001;79:547-68.
3. Mills CD. M1 and M2 Macrophages: Oracles of Health and Disease. Crit Rev Immunol 2012;32:463-88.
4. Das LM, Binko AM, Traylor ZP, Peng H. Lu KQ. Vitamin D improves sunburns by increasing autophagy in M2 macrophages. Autophagy 2019; 15:813-26.
5. Scott JF, Das LM, Ahsanuddin S, Qiu Y, Binko AM, Traylor ZP, et al. Oral vitamin D rapidly attenuates inflammation from sunburn; an interventional study. J Invest Dermatol 2017;137:2078-86.
6. Nguyen CV, Zheng L, Lu KQ. High-dose vitamin D for the management acute radiation dermatitis. JAAD Case Rep 2023;39:47-50.
7. Nguyen CV, Lu KQ. Vitamin D3 and its potential to ameliorate chemical and radiation induced skin injury during cancer therapy. Disaster Med Public Health Prep 2024;18:e4.
8. Nguyen CV, Zheng L, Zhou XA, Ernst MK, Kye Y, Choi JN, et al. High-dose vitamin D for the management of toxic erythema of chemotherapy in hospitalized patients. JAMA Dermatol 2023;159:219-22.
9. Gribonika I, Band VI, Chi L, Perez-Chaparro PJ, Link VM, Ansaldo E, et al. Skin autonomous antibody production regulates host-microbiota interactions. Nature 2025; 638:1043-53.
10. Bousbaine D, Bauman KD, Chen YE, Lalgudi PV, Nguyen TTD, Swenson JM, et al. Discovery and engineering of the antibody response to a prominent skin commensal. Nature 2025;638:1054-64.
11. McGrath JA. Recently discovered roles for macrophages in human skin development. Br J Dermatol 2025; 192:371-2.
12. McGrath JA, Lu KQ. Single high-dose vitamin D3: a promising sunburn therapy. Br J Dermatol 2025; 192:181-2.
13. McGrath JA, Kabashima K. Unlocking the skin's immunological secrets: antibodies and new topical vaccination strategies. Br J Dermatol 2025; in press. doi: 10.1093/bjd/ljaf014. PMID: 39761689.
