|Year : 2021 | Volume
| Issue : 2 | Page : 73-75
The role of the mast cell in pigmentation disorders
Valdemar Wendelboe Nielsen1, Simon Francis Thomsen2
1 Department of Dermato-Venereology & Wound Healing Centre, Bispebjerg Hospital, Copenhagen, Denmark
2 Department of Dermato-Venereology & Wound Healing Centre, Bispebjerg Hospital; Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
|Date of Submission||13-Apr-2021|
|Date of Decision||17-May-2021|
|Date of Acceptance||19-May-2021|
|Date of Web Publication||22-Jul-2021|
Valdemar Wendelboe Nielsen
Department of Dermato-Venereology and Wound Healing Centre, Bispebjerg Hospital, Bispebjerg Bakke 23, 2400 Copenhagen NV
Source of Support: None, Conflict of Interest: None
The mast cell is a critical mediator of the inflammatory response by secreting histamine. While histamine is currently not regarded as a melanogen, recent studies have shown histamine release to induce melanogenesis, melanocyte proliferation and migration. Herein, we discuss the current evidence of the complex relationship between the mast cell and melanocyte, and its impact in pigmentation disorders.
|How to cite this article:|
Nielsen VW, Thomsen SF. The role of the mast cell in pigmentation disorders. Pigment Int 2021;8:73-5
| Introduction|| |
The mast cell plays a pivotal role in the body’s immediate immune response. However, mast cell surplus or overactivation causes an increased histamine release triggering an autoimmune allergic response, as seen in, respectively, mastocytosis, and urticaria and atopic dermatitis. Increased mast cell count is also reported in the pigmentation disorder melasma, with a possible association between increased histamine levels and hyperpigmentation of the skin. In this study, we provide a brief overview of the relationship between the mast cell and the melanocyte, and the role of the mast cell in pigmentation disorders, including the influence of histamine on melanogenesis.
| Background|| |
The mast cell is closely concentrated around capillaries, with large amounts present in the dermis, and is rich in histamine granules, promoting an inflammatory reaction when secreted. The melanocyte, located in the epidermis, produces melanin, a polymerization product of tyrosine. The melanogenesis, therefore, depends on the enzyme tyrosinase, which is stored in the melanosome of the melanocyte. When the melanosome fills with melanin and protein, it turns into a melanin granule, which is phagocytized by keratinocytes. The dendrites of the melanocyte provide an important framework, necessary for the melanocyte to transfer the melanin granule to surrounding keratinocytes, thus increasing pigmentation of the skin. The number of melanocytes depends solely on mitosis of existing melanocytes postnatally and decreases with older age.
| Effect of histamine on melanogenesis|| |
Melanin synthesis is triggered by melanogens, a large group of melanocyte-stimulating factors, including several inflammatory mediators. Previous studies report an increase in the melanin synthesis of cultured melanocytes when stimulated with histamine; however, the signaling pathway and specific cause of increased synthesis is still controversial. For this reason, histamine has not been regarded as a direct melanogen. Melanocytes cultured for 2 days with histamine at concentration of 0.1, 1.0, or 5 μM showed a dose-dependent response of their tyrosinase activity, reaching a plateau at 10 μM. Histamine caused the melanocyte to enlarge and the dendrites both increased in numbers and appeared to be more extended 6 h after the stimulation with histamine.
The morphologic changes and increase in tyrosinase activity are supported in a study by Yoshida et al. showing histamine-induced melanogenesis of cultured human melanocytes. The melanogenic activity was specifically mediated by activation of the H2 receptor, determined due to an increase of cyclic adenosine monophosphate (cAMP) in the histamine-treated melanocytes. This caused a concomitant increase in melanin content, suggesting histamine as a potent melanogen. The stimulatory effects of histamine were completely inhibited by an H2 antagonist, famotidine, where dimaprit, an H2 agonist, induced the same degree of melanogenesis as histamine.
There are four known histamine receptors, all part of the G protein-coupled receptor class. Activation of the H2 receptor, usually associated with gastric acid stimulation and vasodilation, leads to stimulation of adenylyl cyclase causing an increase in cAMP concentrations, resulting in the activation of protein kinase A-signaling pathway. cAMP therefore acts as an important H2 messenger, which also indicates involvement of the H2 receptor in cell growth and differentiation.
| Melanocyte proliferation and melanosome migration|| |
A more recent study by Kim and Lee showed that histamine had a more profound effect on melanocyte proliferation rather than melanogenesis through the H2 receptor, with the number of melanocytes reaching a 2.8-fold increase after 7 days using a fixed 10,000 μM concentration of histamine. Both histamine and the H2 receptor agonist, amthamine, significantly stimulated melanocyte migration, increasing the speed, and a twofold number of migrating cells compared to controls. Histamine improved keratinocyte survival in vitiligo as well. Proliferation and melanocyte migration from neighboring normal epidermis are powerful tools to repigment and treat pigmentation disorders such as vitiligo, where melanocytes are targeted by multiple auto-immune factors leading to a reduction of pigment cells and eventually to complete apoptosis. Recovery depends on a viable melanocyte reservoir and in many patients, repigmentation is possible when melanocytes are stimulated with appropriate topical or oral medications. The expression levels of the H2 receptor are significantly reduced in depigmented compared to normally pigmented epidermis. Based on these findings, an approach using H2 receptor agonists to stimulate melanogenesis and melanocyte migration may be a viable treatment option in patients with vitiligo. However, in the pathogenesis of a particular type of vitiligo characterized by diffuse hypopigmented patches with significant pruritus, histamine appears to play a significant role as a toxic mediator. Blood levels of histamine in patients with vitiligo were significantly increased compared to controls, emphasizing the complex relationship.
| The effect of histamine in hyperpigmentation|| |
As histamine is a known mediator of inflammation, a role of histamine in postinflammatory hyperpigmentation has been suggested. Melasma, one of the most common hyperpigmentation disorders, is an acquired hypermelanosis characterized by asymmetric, brown-colored macules on sun-exposed areas of the skin, especially the face. The pathogenesis has not been fully elucidated, but it is believed to be caused by ultra-violet (UV) light radiation, female hormones, and genetic background. The number of mast cells is shown to be higher in lesional skin than in unaffected skin. As UV exposure triggers the release of histamine from these mast cells, a downstream effect of melanogenesis, proliferation, migration, and elongation and increase in the number of dendrites of melanocytes is initiated. Histamine therefore plays a considerable role in the link between the inflammatory process in UV radiation and the hyperpigmentation that follows.
| Conclusion|| |
The relationship between the mast cell and melanocyte is complex and the research is sparse. Increased concentration of histamine released from mast cells is associated with melanogenesis through the H2 receptor, migration, and morphologic changes such as increased dendricity and proliferation of melanocytes. Similar actions are seen after exposure to UV radiation, indicating UV-triggered histamine release may be the main driver of hyperpigmentation. These effects of histamine on the melanocytes as well as the vitiliginous keratinocytes, may provide the basis for the use of histamine in repigmentation in patients with vitiligo. Further studies focusing on the use of histamine release to treat vitiligo through the tyrosine pathway and antihistamine-specific treatment for hyperpigmentation and melasma may expand the therapeutic options for these challenging pigmentation disorders.
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Conflicts of interest
There are no conflicts of interest.
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