Urticaria presents as transient swellings or wheals caused by plasma leakage. The primary effector cell in the pathogenesis of urticaria is the mast cell [5]. Neuropeptides such as SP, VIP and somatostatin active mast cells to secrete histamine and other mediators that induce urticaria and mediate the late-phase response [5, 80]. SP and CGRP exert effects in cases of chronic urticaria and ACTH is present in the cutaneous mast cells of patients with urticaria pigmentosa [81, 82]. The expression of the POMC gene in mast cells suggests that α-MSH may be contributing to the cutaneous hyperpigmentation seen in patients with urticaria pigmentosa [83]. These studies suggest an interrelationship between the cutaneous nervous system and mast cells in the pathophysiology of urticaria.

Pruritus is one of the most common symptoms encountered in dermatology and significantly impacts quality of life. Itch may be peripheral (dermal or neuropathic) or central (neuropathic, neurogenic or psychogenic) in origin. Neuropathic itch originates at any point along the afferent pathway and is the result of damage to the nervous system whereas neurogenic itch is induced centrally. In the skin, itch is induced by the stimulation of specialized C-fibers by various pruritogens. This is followed by the release of neuropeptides from the cleavage of type-2 proteinase-activated receptors (PAR-2) by tryptase to release histamine, CGRP and SP [84].

It is important to understand the underlying mechanisms to provide effective management and treatment. Multiple cutaneous mediators such as histamine, prostanoids, cytokines and kinins induce pruritus [80]. Pruritus-inducing mechanisms of these mediators include nerve fiber sensitization and receptor stimulation, direct pruritogenic effects and mast cell activation [7]. Histamine is well known for its pruritic effects, especially in urticaria. However, in conditions such as atopic dermatitis the inability of antihistamines to eliminate itch suggest that other mediators are involved as well. Intradermal injection of SP, VIP and somatostatin evokes pruritus; however, CGRP does not have pruritogenic effects in humans [80]. SP is released from C-fiber nerve terminals by the action of mast cell tryptase on PAR-2 in the terminals to directly cause itching and by inducing mast cells to release histamine. Lesional skin in chronic pruritus demonstrates a predominance of dermal SP-containing nerve fibers relative to sympathetic nerve fibers [85]. Additional studies have shown that the pruritic lesional skin of patients with psoriasis contained an increased number of both SP-positive nerves and NK₂ receptor-positive cells. These data suggest that antagonizing the SP receptors NK₁ and NK₂ may be useful in treating patients with pruritic skin disorders [86].

Experimental evidence suggests that the itch circuitry responsible for chronic pruritus may be under tonic inhibitory control by specific types of sensory neurons that are sensitive to mechanical stimulation [87]. These effects are thought to be mediated by members of the TRPV1 family of ion channels [87]. In a murine model, toxin-mediated ablation of GRP- and neuromedin B receptors was associated with abolition of scratching behavior after intradermal application of various pruritogens [88, 89].

There are continuing new developments surfacing in the understanding of the pathogenesis of pruritus including the identification of IL-31 as a role-player in inflammation and pruritus [90]. IL-31 is a known product of mast cells as well as Th2 cells [88]. Interestingly, blood levels of IL-31, CGRP, and SP were recently found to be significantly higher in psoriasis patients than in a control group while the level of CRH was reduced [82]. After 20 treatments with narrow-band UVB radiation, the IL-31 level was significantly reduced, suggesting a possible role in some manifestations of psoriasis [91]. IL-31 levels are also reportedly increased in the serum of patients with chronic urticaria and atopic dermatitis [88]. IL-31 receptors have been found on DRG neurons, suggesting that IL-31 may directly activate these sensory nerve fibers, and perhaps offering an explanation for its role in inducing the sensation of itch [88].

Atopic dermatitis (AD) is characterized by cutaneous hyper-reactivity to nonspecific stimuli leading to a cycle of pruritus, scratching and further worsening of skin lesions [92]. AD is characterized by increased amounts of Th2-derived cytokines [93], as well as an increased density of nerve fibers and neuropeptide levels in the various stages of skin lesions seen in this condition [94]. The diameter of these fibers are larger than those in nonatopic control subjects possibly due to keratinocyte-derived, nerve growth factor (NGF) [95]. The free nerve endings in the skin of atopics also lack a surrounding sheath of Schwann cells suggesting an active state of excitation [94].

SP is a potent pruritogenic neuropeptide in AD that, along with CGRP, is down regulated by phototherapy [96, 97]. An increase in nerve fibers containing SP and CGRP is often observed although Fantini et al. demonstrated a decrease in SP and an increase in VIP levels in chronic lesions of AD [98, 99]. In lesional skin of AD and nummular dermatitis patients, SP and CGRP, but not VIP, fibers in the dermis are elevated compared to nonlesional controls, and are likely maintained by an increased number of mast cells [100]. Intradermal SP increases nitric oxide and enhances SP-induced pruritus while acute stress triggers SP-induced cutaneous mast cell degranulation [7]. Elevated VIP was found to be present in eczema [101].

Plasma levels of NGF and VIP are reportedly higher in patients with AD than in psoriatic patients and healthy controls [102]. SP plasma concentrations were higher in a specific sub-group of AD patients with “extrinsic AD,” a definition that referred to patients who presented with IgE-mediated sensitization to common food and/or aeroallergens based on skin prick tests and/or elevated total IgE serum levels [102]. Investigators using a skin model based on the coculture of human dermal fibroblasts, keratinocytes and porcine DRG neurons found that neural-derived CGRP enhanced both keratinocyte proliferation and epidermal thickness, phenotypic changes consistent with the atopic phenotype. This isolate skin cell model reportedly allowed investigators to study the interaction of nerve and skin cells under defined conditions in which the effects of porcine neurons, which are most similar to their human counterparts, could be assessed. Interestingly, a thicker epidermis was seen when keratinocytes came from atopic skin [103]. These results were interpreted as demonstrating that epidermal nerve endings enhance the morphologic changes associated with the atopic phenotype [103]. Pharmacologic inhibition of CGRP signaling, but not SP signaling, reversed the atopic phenotypic changes. The strong effects of neuronal integration appeared to be mediated by upregulation of CGRP receptor mRNA components in both healthy and atopic models. These data may suggest a relationship between the skin barrier dysfunction characteristic of AD and abnormal CGRP signaling [103].

Allergen-induced late-phase reactions in patients with AD sensitive to a known allergen have been associated with infiltrates of inflammatory cells expressing CGRP and VEGF, suggesting a role of these compounds in mediating the erythema and inflammation that may be associated with allergic inflammation [104]. In situ hybridization revealed that neutrophils and T cells were the predominant CGRP-producing cells in late-phase edema [104]. Studies comparing these results with patients that have allergic diatheses, but not AD, do not appear to have been performed.

Evidence suggests that there may be a relationship between atopic dermatitis and its associated psychological symptoms, including anxiety and depression, which may be accounted for by cutaneous neuropeptide activity. One study demonstrated that SP and NGF are useful serum markers of disease activity in patients with AD, which was evaluated clinically using three different scoring systems [105]. Indeed, in another study NGF-reactive cells were detected more abundantly in epidermal and dermal AD-involved skin [106]. NPY-positive cells were also detected in greater abundance in the epidermis of patients with AD compared to healthy controls. Investigators reported that pruritus in patients with AD was positively correlated with state and trait levels of anxiety, and hypothesized that anxiety may induce pruritus through NPY- and NGF-dependent mechanisms in the skin that are believed to involve mast cells, fibroblasts, lymphocytes and eosinophils [106].

Recently, inherited mutations in filaggrin have been appreciated for the role they may play in AD pathogenesis. Filaggrin (filament-aggregating protein) and its precursor profilaggrin are among the main components of the F-type keratohyaline granules that comprise the stratum granulosum, and as such, filaggrin plays an integral role in maintaining skin hydration [107]. The relationship of filaggrin to AD appears to involve the role it plays in maintaining epidermal barrier function, the integrity of which is known to be lost in many patients with AD. There are more than 45 known mutations in the filaggrin-encoding gene, FLG, at least four of which are believed to contribute to AD pathogenesis [107, 108]. The most common loss-of-function mutation in FLG is found in almost one-third of European Caucasian patients [109]. However, the four recurrent FLG mutations associated with AD only have an estimated combined allele frequency of approximately 7–10 % [108], and at least 50 % of AD patients have no FLG defects [107]. Furthermore, patients with FLG mutations may develop other conditions, such as ichthyosis vulgaris, without developing AD [107]. Recent evidence suggests that the relationship of preexisting FLG mutations and AD development may be related to the expression of immune modulators such as thymic stromal lymphopoietin (TSLP), which is known to be involved in initiating allergic inflammatory responses [110]. Interestingly, keratinocytes that differentiate in the presence of Th2 cytokines show a lower filaggrin protein expression, independent of underlying FLG mutations [109]. The established role of neuropeptides in regulating the aberrant cutaneous immune responses seen in AD suggests that the pathogenesis of this disorder is multi-faceted and involves a complex interaction between nerve-derived signaling molecules, Th2-type immune responses and abnormal skin barrier function.

Psoriasis is a multifactorial disease characterized by symmetric plaque lesions. The possibility of a neurogenic component is supported by the temporal onset or exacerbation of lesions with emotional stress, the appearance of lesions at sites of injury or trauma (Koebner phenomenon – believed to be initiated by the release of proinflammatory neuropeptides in traumatized skin) and by observations that lesions resolve in areas of denervation or following central nervous system lesions such as ischemic stroke [80, 111].

NPs and sensory nerve density are increased in lesional skin [80]; however, levels of SP and VIP vary in psoriasis. Elevated levels of both SP and VIP [112], normal SP and elevated VIP [101] and increased SP and normal VIP levels [113] have all been demonstrated in psoriatic lesions. There are conflicting reports of CGRP expression in lesional and nonlesional skin compared to normal controls. Moreover, VIP expression is reported to be increased, yet a statistical difference is not consistently observed between lesional and normal skin [111]. Serum CGRP and VIP are both reportedly elevated in psoriatic individuals. Treatment with anthralin or psoralen plus long-wave UVR [UVA radiation (320–400 nm)] (PUVA) led to a decrease in serum VIP while CGRP remained elevated [114]. Below we discuss evidence that VIP may be involved in biasing immune responses toward the Th17 pole, which suggests the potential relevance of these findings to enhancing the current understanding of psoriasis pathogenesis. Compared to psoriatic lesions, a lower level of SP is seen in lichen planus and lichen simplex chronicus while higher levels are observed in spongiotic dermatoses [113]. Serum beta-endorphin is elevated in psoriatic patients and is likely produced by inflammatory cells within psoriatic plaques [115]. PACAP-38 is also increased in lesional psoriatic skin and recent evidence suggests NGF is involved in the pathogenesis of psoriasis [28, 80]. Keratinocyte hyperproliferation is a histologic feature in psoriasis and NGF is suggested to induce keratinocyte proliferation and prevent apoptosis [111]. SP reportedly upregulates keratinocyte-derived IL-32 and mast-cell-derived tryptase in psoriatic lesional skin [116]. Additional evidence for neuropeptide-mediated mast cell involvement in psoriasis pathogenesis comes from investigations revealing that SP stimulates mast cells to increase CRH receptor (CRHR-1) expression, which in turn enhances NK₁ gene transcription, mediating SP signaling [117]. Overstimulation with CRH, as in chronic stress, reportedly leads to down-regulation of CRHR-1 on the surface of mast cells, which may account for previous observations of decreased CRHR-1 gene expression in psoriatic lesional skin [117]. Together, these data may account for the relationship of stress-induced activation of the hypothalamic-pituitary-adrenal axis to psoriasis flares.

Novel murine models of psoriasis have enabled further studies of the role of neurocutaneous immunity in the pathogenesis of this disorder. The KC-Tie2 murine model is engineered to overexpress the angiopoietin receptor Tie2 in keratinocytes [32]. Tie2 receptor activation is associated with reactive oxygen species generation, which may mediate keratinocyte proliferation via VEGF production and angiogenesis [118]. KC-Tie2 mice spontaneously develop features characteristic of human psoriasis including increased numbers of dermal CD4⁺ T cells, epidermal CD8+ T cell infiltrates and pro-inflammatory cytokines such as IFN-γ, TNF-α, IL-1α, IL-6, IL-12, IL-22, IL-23 and IL-17 [118]. In this model, systemic administration of the T-cell calcineurin inhibitor cyclosporin A was associated with significant improvement in the psoriasiform phenotype and a reduction in lesional T cells and their associated pro-inflammatory cytokines, an observation consistent with the role that T lymphocytes are believed to play in psoriasis pathogenesis [118]. In these experiments, antigen presenting cells remained high in lesional skin, which may have accounted for incomplete resolution of the disease phenotype [118]. In fact, clodronate-liposome-mediated depletion of antigen presenting cells in KC-Tie2 mouse skin was associated with resolution of the acanthotic skin phenotype, decreased dermal angiogenesis and normalization of the levels of multiple pro-inflammatory cytokines.

Additional investigations using the KC-Tie2 model revealed that denervation of cutaneous sensory nerves led to significant drops in lesional dendritic and CD4⁺ T cells, reminiscent of denervation in human patients with diseases of the nervous system. However, administration of an SP agonist prevented decreases in CD11c⁺ and CD4⁺ cells, but had no effect on acanthosis [119]. Interestingly, administration of CGRP reversed the improvement in acanthosis and prevented the denervation-mediated decrease in numbers of CD4⁺ cells [119]. Perhaps the relationship of sensory nerve activation to disease activity, i.e. secondary to external stimulation such as pressure, may partially contribute to the aforementioned Koebner phenomenon [119].

The imiquimod mouse model of psoriasis uses a toll-like receptor (TLR) 7 agonist to induce a psoriatic phenotype [120]. Investigators using this model to study the pathogenetic mechanisms of psoriasis found that IL-23-mediated activation of IL-17 and IL-22 cells was requisite in triggering the psoriasiform phenotypic changes characteristic of this model [120]. Additional investigations found that IL-22, a cytokine produced by Th1, Th17 and Th22 cell populations as well as by innate immune cells, is required for the imiquimod-induced psoriasiform inflammatory changes characteristic of this murine model, supporting the known role of these novel T cell populations in triggering psoriasis [121]. Recent evidence suggests that nociceptive sensory neurons expressing specific ion channels including TRPV1 are essential for driving this inflammatory through stimulating dermal dendritic cell to produce IL-23 which, in turn, induces dermal gamma-delta T cells to produces IL-23-dependent inflammatory cytokines [122]. Accordingly nociceptive sensory neuron loss was associated with a reduction in both local swelling and inflammatory infiltrates [122]. Furthermore, imiquimod treatment was associated with increased levels of IL-17A, IL-17F and IL-22, consistent with previous reports demonstrating the role of these cytokines in psoriasiform inflammation [122]. Finally, recent experiments have demonstrated that cutaneous denervation results in the loss of imiquimod’s ability to induce the psoriatic phenotype, highlighting the essential role of cutaneous nerves and the neuropeptides they secrete in triggering this skin disorder [123].