Ultraviolet radiation (UVR) has effects on the skin both in the longer (UVA) and in the shorter (UVB and UVC) wavelength ranges 13 and is thus capable of affecting dermal MCs directly or indirectly. The effects of UVR on the skin include reddening, sunburn and tanning, vitamin D synthesis and the development of skin cancers, 14 all of which may involve skin MCs. At the cellular level, exposure of the skin to UVR also results in a large and diverse set of responses of cutaneous cells such as proliferation, 15 , 16 differentiation, 17 apoptosis, 18 the release of mediators, 19 - 23 and the expression of miRNA profiles. 24 , 25 Skin MCs may be affected by these effects of UVR directly and indirectly, and they may be involved as intermediaries of UVR effects on other skin cells.

Mast cells (MCs) were first described by Paul Ehrlich in 1878 as metachromatic, granulated cells. 1 MCs can release a huge variety of soluble preformed or newly‐synthesised mediators, including proteases, histamine, lipid mediators, cytokines and chemokines (reviewed in 2 ). MCs are preferentially located at body surfaces such as the skin, where they induce allergic reactions and contribute to many other immune and inflammatory responses. 3 - 6 In addition, skin MCs participate in tissue remodelling and repair 7 , 8 as well as in wound healing. 9 The biology of skin MCs and cutaneous MC responses are influenced by the effects of environmental factors including ultraviolet (UV) radiation (UVR). The number of skin MCs in humans, for example, is higher in sun‐exposed areas as compared to sun‐protected skin, 10 , 11 and MC numbers in the superficial layers of the skin have been shown to be up to 10 times higher than in the subcutis. 12 Exploring the effects of UV light on cutaneous MCs (Figure 1 ) can help to better understand their biology and functions, and may allow for the targeted modulation of their effects on the skin.

In recent years, vitamin D has been linked to MC‐induced immunosuppression in response to UV exposure, and MCs produce the immunosuppressive cytokine IL‐10 and limit skin reactions in response to UVB in mice. 29 Interestingly, murine MCs express functional vitamin D receptors, which are required for the synthesis of IL‐10 in response to 1α,25(OH) 2 D 3 . 41 Human and mouse MCs also express 25‐hydroxy vitamin D‐1α‐hydroxylase (CYP27B1), which converts 25OHD 3 to active 1α,25(OH) 2 D 3 . 42 These vitamin D metabolites can decrease IgE‐dependent proinflammatory MC mediator production through a vitamin D receptor‐dependent mechanism in vitro. 42 Thus vitamin D seems to be a key determinant in the proinflammatory or immunosuppressive phenotype of skin MCs.

The mechanisms that underlie the effects of UVR on skin MCs are not well understood and are yet to be fully characterised. As shown in Table S1 and Table S2 , there is inconclusive evidence on the effects of UVR on MCs both ex vivo and in vivo. This unsureness has certainly an impact on our current understanding of the details of the possible mechanisms. However, there are several studies showing mediators involved in skin UV‐responses and affecting MCs. Endothelin‐1 33 and cis‐urocanic acid 34 can induce the degranulation of MCs. Treatment of mice with ketotifen, a mast cell stabiliser, has been shown to significantly reduce UV‐induced wrinkle formation. 35 In addition, alternative complement component factor B was recently shown to regulate UVA‐ and UVB‐induced immunosuppression and MC infiltration into the skin in mice. 28 UV‐induced skin‐derived platelet‐activating factor (PAF) induces MC migration from the skin to the draining lymph nodes, mediating immunosuppression. 36 PAF also increases p300 histone acetyltransferase expression and activates acetylation of CXCR4 promoter in mast cells, thus causing epigenetic modifications. 37 Interestingly, PAF has also been found to reduce proliferation and DNA repair in mast cells. 38 MCs, like keratinocytes, fibroblasts and several other cutaneous cells are also susceptible to low doses of narrowband (NB) UVB, making them targets of photons that lead to DNA damage and apoptosis. 39 NAD(P)H oxidase 2 has been found important in UVA‐induced calcium oscillations and mediator production of mast cells. 40 Whether or not MCs express photoreceptors, such as cryptochromes or opsins, remains to be investigated in detail.

In addition, UVR was assessed for its effects on MC numbers. Most, but not all of the studies on UV‐induced changes in murine MC numbers in vivo showed an increase, 26 - 30 some found no change of skin MC numbers, 31 , 32 partly perhaps because of the use of different mouse strains and UVR exposures in these studies (Table S2 A).

UVR has also been investigated for activating effects on skin MCs in vivo, both in mice and in man. These studies, however, are limited in number and yielded inconclusive results in regard to skin swelling, but point to MC degranulation and mediator release (Table S2 A). The number of studies on the effects of UVR on activated mast cells in vivo is also very limited. Their results were, again, variable and inconclusive in relation to skin swelling, wheal‐and‐flare responses and MC degranulation (Table S2 B). This is most probably due to different MC activators and species used in these studies.

In addition, several studies have shown that UVR can reduce the release of histamine by activated MCs ex vivo (Table S1 B). The inhibition by UVR of induced histamine release has been shown in MCs from rodents and humans, obtained from the skin and other sources, and stimulated with various activators including compound 48/80, the calcium ionophore A23187, anti‐IgE and substance P (Table S1 B).

Most studies of the effects of UVR on MCs ex vivo have looked for histamine release by MCs in response to UVR (Table S1 A) or the effects of UVR on histamine release by activated mast cells (Table S1 B). A direct comparison of study results is difficult due to differences in the source of MCs investigated (rodent vs human; peritoneum vs skin vs MC line), the type of UVR used (UVA vs UVA1 vs PUVA vs UVB) and the UVR doses employed in the different studies. Both UVA and UVB appear to be able to activate MCs and induce histamine release ex vivo (Table S1 A). However, the number of studies is limited and clear conclusions on the reproducibility of the results, the dose dependency and kinetics of this effect and differences in the response of different MC populations require further studies.

3 THE ROLE OF MAST CELLS IN UV‐DRIVEN DISEASES

3.1 Polymorphic light eruption and sunburn Polymorphic light eruption (PLE) is a common photosensitivity disorder affecting mainly young adult women during spring and summer. PLE presents with itchy papules and patches on sun‐exposed skin. MCs have been suggested to play a role in PLE, and their number in the papillary dermis is increased after photohardening with PUVA.43 Along with this, MC‐ deficiency is associated with UV‐provoked itching.44 Including the data on MCs and UV tolerance (see below), it is possible that MC dysfunction is important in the development of PLE.45 It is obvious that this intriguing topic awaits further investigations. Sunburn, although usually not considered as a classical disease, is the immediate effect of excessive UV exposure on the skin, presenting with skin erythema and oedema, pain, and, in extreme cases, blistering. The role of MCs in acute sunburn has not been widely studied, but there are several independent lines of evidence that suggest that they do play a role. For example, human skin exposed to erythema‐inducing doses of UVA shows MC hypogranulation,46 and human skin MCs have been found to degranulate in response to UVB exposure and to release TNF‐α during acute sunburn.47 In a mouse model, the complement component factor B was found to regulate UV‐induced oedema and also MC infiltration into the skin.28 In addition, cutaneous levels of endothelin‐1 are reportedly increased during UV‐induced skin inflammation, leading to MC degranulation and MC‐dependent inflammation.33 However, further research is needed to clarify the exact role and mechanism of MC effects in sunburned skin.

3.2 Solar urticaria Solar urticaria (SU) is a UVR‐driven MC disorder. It is characterised by itchy wheals at the sites of UV irradiation (most commonly UVA) that occur within minutes after exposure. In patients with SU, cutaneous MC counts have been reported to be increased.48, 49 More importantly, the signs and symptoms of SU are held to be due to the degranulation of skin MCs, and elevated blood levels of histamine have been observed in patients with SU.50 The mechanisms of MC activation in SU are unclear. One of the hypotheses is that a UV‐induced photoallergen is recognised by IgE bound to cutaneous MCs, which then induces their degranulation and histamine release in response to UV. This notion is supported by the fact that the injection of autologous preirradiated serum into the skin of patients with SU can lead to a whealing51-53 as well as recent reports that anti‐IgE treatment with omalizumab can be of benefit in patients with SU.54-57 The UV action spectrum varies between patients with SU,58 and it has been suggested that there exist both activating and inhibiting UV spectra, inducing and preventing the wheal formation in SU, respectively.58-61 Exposure to inhibiting UV spectrum light may block the binding of the photoallergen to MCs,62 and there might be a blockade of photoallergen binding to IgE on MCs also during UV‐induced tolerance.63 The induction of UV tolerance (photohardening) can reduce SU symptoms, but the exact mechanisms of action remain unclear. Recently, MC‐deficient mice were found to be resistant to photohardening treatment, suggesting that MCs may be necessary for the induction of phototolerance.44 In one of the earliest studies, tolerance in patients with SU was achieved by graded whole body exposures to 320‐400 nm UVA.64 However, the density of MCs was not decreased in irradiated tolerant sites nor was the response to i.d. injected histamine or codeine, a MC degranulator, changed after the induction of UV tolerance. This indicates that mechanisms other than MC or MC mediator depletion or histamine tachyphylaxis must be involved.64 UVA has been efficiently used to achieve tolerance with a short 2‐ or 3‐day protocol,63, 65 and the results seem to be long‐lasting.63 Also NB‐UVB UVR was reported to be effective in the treatment of SU.66

3.3 Cutaneous lupus erythematosus Cutaneous lupus erythematosus (CLE) is characterised by erythematous hyperkeratotic plaques at sites of sun exposure such as the face and dorsum of the hands. In CLE, the exact pathological mechanism is not yet known, and for the present, the effects and the role and relevance of MCs in CLE are controversial. A mouse model of spontaneous lupus‐like symptoms showed an accumulation of MCs in the lesional dermis and prolonged histamine effects due to impaired histamine metabolism.67 Skin MC numbers were also reported to be increased in patients with CLE, and keratinocytes exposed to UVB induce MC migration68 indicating a role for MCs in CLE pathology. However, MC deficiency did not change the phenotype, nor alter the autoantibody production in lupus‐like mice69 suggesting that MCs are dispensable for disease onset.