It became apparent that histamine exacerbates allergic dermatitis through experiment with histamine-deficient mice. Histamine induces infiltration of inflammatory cells and epidermal hyperplasia in chronic allergic dermatitis. Histamine also induces itchy sensation as well as other pruritogens in allergic dermatitis. Many kinds of cells in the skin express histamine receptors and allergic responses are induced through histamine H 1-4 receptors, especially H1 and H4 receptors.

Keywords: Histamine, Contact dermatitis, Atopic dermatitis, Eczematous lesion, Scratching, Four histamine receptors

INTRODUCTION

Inflammatory skin diseases, including contact dermatitis and atopic dermatitis (AD), are often characterized by inflammation with pruritus. A major mediator of inflammation and pruritus is histamine. Histamine is a ubiquitous chemical messenger through four pharmacologically distinct receptors. This review summarizes the findings regarding the roles of histamine and four histamine receptors on the development of eczematous lesion and pruritus in allergic dermatitis.

Eczematous Lesions Developed by Histamine in Murine Allergic Contact Dermatitis

Mast cells and basophils mainly secret histamine in the skin. Assessing the effect of histamine in development of eczematous lesions, recognizing in contact dermatitis and AD, in vivo has been difficult, as most observations involve the use of histamine receptor antagonists. Histamine- deficient mice by disrupting the histidine decarboxylase (HDC) gene to solve these problems were produced [1].

Plasma extravasation induced with compound 48/80, an immediate-type response, is produced in HDC (+/+) mice but not in HDC (-/-) mice. On the other hand, contact hypersensitivity, a delayed-type response, is observed as a thickening of the ear skin after 2,4,6-trinitro-1- chlorobenzene challenge and shows no difference between HDC (+/+) and HDC (-/-) mice [2]. Contact hypersensitivity is elicited by single epicutaneous applications of contact sensitizing agent in mice previously sensitized with the same agent. However, contact dermatitis in human usually causes by repeated epicutaneous application of various antigens including contact sensitizing agents and environmental allergens. Repeated epicutaneous application of contact sensitizing agent induces epidermal hyperplasia, accumulation of large numbers of mast cells and CD4+ T cells beneath the epidermis, and elevated serum levels of antigen-specific IgE, similar to observations of AD [3,4]. Contact hypersensitivity response is shifted from a delayed- type hypersensitivity to an immediate-type response by repeated application [5].

The role of histamine in the extent of chronic eczematous lesions induced by repeated application of  contact sensitizing agent was investigated by using HDC (-/-) mice. Daily application of diphenylcyclopropenone induces chronic allergic contact dermatitis (CACD) in mice. Histological examination of the skin reveals that mice display hyperplastic epidermis and mast cells and CD4+ T cells infiltration. The magnitude of hyperplastic epidermis and inflammatory cells is more significant in HDC (+/+) mice than HDC (-/-) ones (Figure 1) [6]. Histamine mediates chemotaxis of mast cells via the H4 receptor and is responsible for mast cell accumulation in allergic tissues. Unique accumulation of mast cells is presumed to be controlled by histamine through H4 receptor binding of mast cells [7]. Infiltration of CD4+ T cells in HDC (+/+) mice is prominent compared to infiltration of HDC (-/-) mice [6]. IL-16, the soluble ligand for CD4+, represents a potent chemoattractant for CD4+ T cells, eosinophils and monocytes, and is mainly derived from activated T cells [8].

IL-16 is therefore thought to be under the control of histamine and plays an important role in the development of cell-mediated immunity, such as delayed-type hypersensitivity reaction [9]. As lymphocytes are stimulated to produce IL-16 by histamine via H4 receptors [10], histamine-induced IL-16 contributes to the development of eczematous lesions in contact dermatitis.

Levels of IL-6 and Macrophage Inflammatory Protein-2, murine homologue of human IL-8, are increased in murine CACD [11]. Histamine enhances IL-6 and IL-8 production in human keratinocytes in vitro [12]. IL-6 enhances B- and T-cell activation and proliferation [13], and stimulates keratinocyte proliferation, resulting in epidermal acanthosis [14, 15]. Keratinocytes express abundant HDC protein and the levels increase in atopic skin [16].

 

Regulatory T cells (Tregs) are a subset of T cells, which regulate effector T cells and lead to immune tolerance to reduction of allergic reactions, and play a role in the maintenance of immunological self-tolerance by actively suppressing self-reactive lymphocytes [17]. Tregs suppress effector T cells and ameliorate contact dermatitis [18]. TGF- β is one of the main regulators of Treg recruitment in allergic lesion [19]. Since the level of TGF-β1 and the number of Tregs in eczematous lesions is significantly higher in HDC (-/-) mice compared to HDC (+/+) mice, histamine suppresses Tregs mediated by TGF-β1 in the skin lesions [20]. The level of IL-10 is also suppressed by histamine in CACD [20]. Since Th2 cell-driven allergic reactions are suppressed through IL-10 production [21], histamine aggravates eczematous lesions by reduction of the level of IL-10.

 

Th17 cells, a distinct lineage of effector CD4+ T cells, are characterized by their production of IL-17 and IL-22 [22]. IL-17 plays an important role in activating T cells in allergen-specific T-cell-mediated immune responses [23]. IL-17 efficiently amplifies the allergic reaction by rendering T cells accessible to recruitment at the site of skin inflammation in allergic contact dermatitis [24]. Th17 cells inhibit IL-4 production by Th2 cells [25]. Infiltration of IL- 17F expressing cells in CACD is suppressed in HDC (+/+) mice compared to HDC (-/-) mice. Levels of IL-17 and IL- 22 of skin lesions decrease in HDC (+/+) mice compared to HDC (-/-) mice (unpublished data). These data indicate that histamine may aggravate skin lesions of CACD by suppressing Th17 cells.

 

Scratching Behavior Induced by Histamine in Murine Allergic Contact Dermatitis

Pruritus has been defined as an unpleasant sensation that triggers a desire to scratch [26]. Contact dermatitis is known as the common skin disease with itch sensation as the typical symptoms and is frequently accompanied by itch-associated scratching behavior in rodents [27]. Examination of mechano-insensitive C-nociceptors has identified C- nociceptors that respond to histamine iontophoresis in parallel with the itch rating [28]. Scratching behavior is observed in HDC (+/+) mice almost not in HDC (-/-) ones after DCP application [29]. Scratching behavior is ameliorated in mice treated with H1 and H4 receptor antagonist [30]. The massively increased itch in lesional skin of patients with AD is based on sensitization for itch in the spinal cord rather than in primary affected neuron [31]. A small number of c-Fos (+) cells, excited sensory cells, are identified in the spinal dorsal horn of HDC (+/+) and HDC (-/-) mice. However, remarkable increase in c-Fos (+) cells is observed to lamina I in the dorsal horn of CACD-developed HDC (+/+) mice, whereas it is not in CACD-developed HDC (-/-) mice. Substance P expression in the spinal dorsal horn increases with peripheral sensory stimulation induced from eczematous lesions [32]. Substance P expression in the spinal dorsal horn is increased only in CACD-developed HDC (+/+) mice. Since substance P is released from peripheral nerves, histamine is responsible for substance P expression in the spinal dorsal horn via peripheral nerves. E- cadherin, one of the synapse-related molecules, is expanded in the spinal dorsal horn by peripheral sensory stimulation induced from allergic dermatitis [32]. E-cadherin expression is increased only in the spinal dorsal horn of CACD- developed HDC (+/+) mice. The nerve fiber proliferation and/or synapse formation might augment itch sensation only in CACD-developed HDC (+/+) mice [29]. Taken together, scratching behavior is mainly mediated with histamine and the afferent pathway of sensation connects with the central nervous system through lamina I of the spinal dorsal horn in murine CACD [29]. Pruritus is known to be induced by a variety of mediators in addition to histamine. Primary sensory nerves transmit the pruritic signal by protease, endothelin-1, IL-4, IL-13, IL-31, chloroquine, and so on [33]. Mas-related G protein-couple receptors and gastrin- releasing peptide receptor (GRPR) mediate the pruritic sensation in primary sensory nerves and dorsal spinal cord, respectively [34,35]. Another characteristic of pruritus in patients with AD is its chronicity. With chronic pruritus, scratching causes skin lesions, which in turn lead to activation of STAT3 in spinal dorsal horn astrocytes. Induction of lipocalin 2 by astrocytes sensitizes a pruritus- processing neuronal network involving GRPR+ spinal dorsal horn neurons, and thereby contributes to the vicious cycle of itching and scratching and chronic pruritus [36]. Th2 cells produce IL-31 and its receptor (IL-31 receptor A) is expressed on primary sensory nerves [37]. Anti-IL-31 receptor A injection inhibits pruritus in AD [38]. IL-33 signaling is functionally present in primary sensory neurons and induces pruritus in poison ivy allergic dermatitis [39]. Plasma levels of substance P are associated with disease activity of AD [40]. Substance P receptor (neurokinin 1 receptor) antagonist reduces scratch behavior in murine allergic dermatitis model [41].

 

Four Histamine Receptors in the Skin

A major mediator of allergic reactions and inflammation is histamine. High amounts of histamine are released during allergic and inflammatory disorders [42]. Histamine is a ubiquitous chemical messenger that displays numerous functions mediated through at least four pharmacological distinct receptors (Table 1).

H1 receptor is expressed in keratinocytes, endothelial cells and peripheral nerves [43]. Histamine augments the production of IL-6, IL-8 and granulocyte-macrophage colony-stimulating factor in human keratinocytes [12,44]. Histamine modulates the differentiation from epidermal keratinocytes and impairs the skin barrier function via H1 receptor [45]. The level of nerve growth factor is higher in AD than in healthy controls and correlated with the severity of itch, erythema, eosinophil count and LDH levels. The nerve growth factor level is decreased by H1 receptor antagonist [46]. Elevated expression of periostin, which is a matricelluar protein and contributes to tissue remodeling, is found in lesional skin from AD patients. Histamine induces the expression of periostin and H1 receptor  antagonist blocks both periostin and collagen expression [47]. High numbers of H1 receptor expressing CD68 + macrophages  are detected in the dermis of AD skin lesions. FcɛRI stimulation promotes the generation of H1 receptor expressing macrophage-like cells with enhanced histamine biosynthesis and H1 receptor-mediated proinflammatory properties [48]. Lack of H1 receptor expression on dendritic cells leads to diminished IL-12, upregulated IL-23, and IL-6 production upon allergen stimulation. H1 receptor engagement on dendritic cells is necessary for dendritic cell activation and subsequent priming of effector IFN-γ + CD8 + T cells [49]. The characteristic features of H1 receptor activation in the skin are exemplified by increased vascular permeability [50] and itching transactions [51]. H1 receptor antagonists have been successfully used as drugs for treating allergic diseases, since these functions contribute to allergic responses [52].

 

The H2 receptor is expressed in keratinocytes, macrophages and lymphocytes [53]. Histamine induces an increase in intracellular Ca2+ of cultured normal human keratinocytes via H2 receptor [54]. H2 receptor stimulates the phospholipase C signaling pathway in mouse keratinocyte [55]. Histamine-induced stimulation of phosphodiesterase 4, which increases in blood mononuclear white cells of patients with AD, is mediated by the H2 receptor and related to intracellular cAMP in the human monocyte cell line [56]. H2 receptor agonist downregulates IL-12p70 production of prestimulated human monocyte-derived dendritic cells [57]. H2 receptor antagonist blocks histamine-induced IL-16 release from human CD8+ T cells [10]. However, its extra function in the skin remains unclear.

 

The H3 receptor is expressed in mast cells and sympathetic and parasympathetic nerves and regulates histamine, serotonin, acetylcholine and other neurotransmitters [58]. H3 antagonist inhibits cutaneous microvascular permeability due to intradermal injections of compound 48/80 [59]. H3 receptor antagonist increases scratching behavior in ICR mice [60] and mast cell-deficient mice [61]. Substance P is involved in the scratching behavior elicited by H3 receptor antagonist [62]. Histamine induces a calcium increase in the skin-specific sensory neurons via activation of the H1 receptor and H4 receptor as well as inhibition of the H3 receptor. The decreased threshold in response to H3 receptor antagonism assumes to activate H1 and H4 receptor on sensory neurons, which in turn results in the excitation of histamine-sensitive afferents and therefore elicits the sensation of itch [63]. However, the exact physiological roles of H3 receptor in the skin remain to be explored.

 

H4 receptor knockout mice show a clear amelioration of the skin lesions, with a diminished influx of inflammatory cells and a reduced amount of IgE, a reduced number of splenocytes and lymph node cells with a decreased number of CD4+ T cells in a chronic model of AD [64]. The H4 receptor is upregulated during differentiation of keratinocytes in the upper layer of epidermis versus keratinocytes in basal layer [65]. H4 receptor is highly expressed on keratinocytes from patients with AD and its stimulation induces keratinocyte proliferation [66]. H4 receptor is also expressed in leukocytes and mast cells [67]. H4 receptor expression on Th2 cells is higher compared with Th1 cells and stimulation of H4 receptor results in an induction of transcription factor AP-1 in Th2 cells,  which are dominant in allergic dermatitis [68]. H4 receptor antagonist inhibits the production of CCL17 and CCL22, Th2 chemokine, in monocyte-derived Langerhans cells in patients with AD [69]. Th17 cells, expressing the H4 receptor, play a potential role in AD and the number of this cell type is associated with the severity of AD in the acute lesions [70]. IL-17 expression is enhanced in AD [71]. Th17 function is one of the important factors regulating allergic diseases such as CACD and AD [72]. Natural killer cells accumulate in eczematous lesions of AD via H4 receptor [73]. Histamine induces chemotaxis of eosinophils through the H4 receptor [74] and rapidly induces shape changes in eosinophils while at the same time enhancing their chemotactic response to chemokines through the H4 receptor [74, 75]. H4 receptor also mediates histamine-induced

chemotaxis of mast cells in mouse [7, 76]. H4 receptor antagonist ameliorates CACD in HDC (+/+) mice, while H4 receptor agonist develops CACD in HDC (-/-) ones [77]. H4 receptor is involved in pruritic responses in mice to a greater extent than H1 receptor [78]. Taken together, these results strongly indicate that H4 receptor antagonism is effective for allergic dermatitis.

 

CONCLUSION

Histamine is related to development of eczematous lesions and scratching behavior in murine allergic contact dermatitis. Since histamine receptors play an important role on allergic dermatitis, anti-histamine receptor agents are effective to treat allergic dermatitis, such as CACD and AD.

 

CONFLICT OF INTEREST

None declared.