Pathophysiology of Itch and New Treatments

Ulrike Raap; Sonja Ständer; Martin Metz

Disclosures

Curr Opin Allergy Clin Immunol. 2011;11(5):420-427. 

In This Article

Pathophysiology of Itch in the Skin: The Role of Immune Cells

The orchestration of itch in the skin appears to be regulated by a complex interplay of many factors and may differ depending on the pathophysiological changes in the skin. Itchy skin diseases, including atopic dermatitis, chronic urticaria, psoriasis and allergic contact dermatitis are associated with increased production and release of cytokines, neurotrophins and neuropeptides possibly leading to the exacerbation of itch.[9] Thus, infiltrating and tissue resident cells can, at least in part, be responsible for the induction or exacerbation of itch (Fig. 1).

Figure 1.

Interplay between tissue resident cells and itch mediators in the inflamed skin
Neuroimmune interaction mechanisms orchestrate the phenomenon of itch. A complex interplay between keratinocytes, mast cells, T-cells eosinophils, superantigen-producing (SAG) staphylococcal colonies (SC) and nerves (N) in the epidermis (E) and dermis (D) of inflammatory skin disease leading to increased release of substance P (SP), nerve growth factor (NGF), neurotrophin (NT)-3, NT-4, brain-derived neurotrophic factor (BDNF), histamine (Hist) and interleukin (IL)-31. Dorsal root ganglion expressing receptors for IL-31 (IL-31RA), neurokinin-1 receptor (NK-1R) and gastrin-releasing peptide receptor (GRPR).

Keratinocytes

As resident cells of the skin, epidermal keratinocytes provide an effective barrier against physical, chemical and biological environmental factors. Thus, keratinocytes are a crucial part of the innate defense system. As described before, induction of itch in the skin is an important defense mechanism to detect and instantly remove possibly harmful substances quickly from the skin by scratching. Therefore, the epidermis has to provide ways for detection of potential threats and for transmitting itch via the production and release of pruritogenic mediators. Further, epidermal keratinocytes are in close connection to sensory nerves within the epidermal part of the skin, assuming a direct interaction mechanism between both cell types (Fig. 1).

Keratinocytes release a battery of inflammatory and pruritogenic substances, which can be induced by various innate mechanisms, for example toll-like receptors, Ultraviolet (UV)-light or thermoreceptors.[10] Keratinocytes are able to detect itch-associated signals by expression of protease-activated receptor-2,[11] opioid,[12] cannabinoid[13] and histamine H4 receptors.[14] By responding to these signals, keratinocytes can modulate itch in many ways. For example, keratinocytes can release neurotrophins including NGF[15,16] and neurotrophin-4[17] (Fig. 1), lipid mediators[18] or endothelin-1,[19] which can either directly activate itch fibres in the skin or activate mast cells to release pruritogenic mediators. In addition, neuropeptides including substance P have been shown to significantly increase the release and production of NGF of human cultured keratinocytes, indicating a neuroimmune interaction mechanism between sensory nerves and keratinocytes[20] (Fig. 1). Interestingly, keratinocytes can also inhibit itch through the release of endocannabinoids, which bind directly to inhibitory receptors on sensory nerves.[13] The regulatory interplay between activating and inhibitory mechanisms of itch in specific disease via keratinocytes is, however, thus far not clear.

Mast Cells

Mast cells are tissue resident cells, which are found in close vicinity to hair follicles, keratinocytes, blood vessels and sensory nerves.[21] Mast cells express a large number of receptors, which can activate the cells to release their mediators.[22]

The best-known mast cell mediator for the induction of itch is histamine. Preformed histamine is present in large amounts in mast cell granules and thus, after cell activation, can be immediately released into the surrounding area in which it induces itch via H1 receptors on nerve fibres. Apart from H1 receptors, histamine appears to modulate itch also by H3 and H4 receptors. The pharmacological blockade of H4 receptors has been shown to significantly reduce itch in mouse models and diminish existing airway inflammation.[14,23••] In the skin, H4 receptors seem to be involved in the inflammatory process because H4 receptors acting on Th cells enhance the production of proinflammatory cytokines as shown in atopic dermatitis.[24,25•] H3 receptors appear to be involved in the suppression of pruritus because H3 receptor antagonists have been shown to induce pruritus in mice.[26]

Apart from histamine, many other mast cell-derived substances have been identified to be involved in the induction or modulation of itch. For most of these substances, the clinical relevance remains, however, to be determined. Among these are proteases, lipid mediators, neuropeptides and various cytokines. Interestingly, skin mast cells of patients with psoriasis are also a source of interleukin (IL)-31, which has been identified for being a potent pruritogenic cytokine (Fig. 1).[27••] Other substances that are not produced by mast cells have been shown to induce or exacerbate itch without directly affecting nerve fibres but through indirect effects as a result of mast cell activation in the skin. Although these are broadly referred to as histamine liberators, the activation of mast cells may also lead to the release of other itch-inducing substances. Among the most relevant mast cell activators in pruritic diseases are neurotrophins such as NT-3,[28] neuropeptides including vasoactive intestinal peptide, calcitonin gene-related peptide, substance P (Fig. 1) and endothelin-1.[19] In this regard, it was shown in a mouse model that a mast cell-mediated allergic reaction is markedly diminished in the absence of sensory cutaneous nerves.[29] Together, many of the mast cell mediators are involved in the elicitation of itch. Thus, mast cells have a central role in the cellular network of itch.

Eosinophils

Itchy skin diseases including atopic dermatitis, allergic contact eczema, chronic urticaria and the scratch-related prurigo nodularis are associated by an increased cellular infiltration of eosinophils. Eosinophils are considered to be predominantly tissue resident cells and do not re-enter the circulation. In humans there are relatively few data on the kinetics of eosinophil trafficking and it is difficult to make firm statements about the relative contribution of eosinophilopoiesis and recruitment into the tissue.[30] Interestingly, eosinophils can be found in close vicinity to nerves.[31]

Eosinophils constitutively express mRNA for NGF and NT-3 (Fig. 1).[32,33] This is interesting, as neurotrophins are capable of inducing the cutaneous nerve sprouting and myelinization of nerves. Direct neuroimmune interactions between eosinophils and nerves have been shown in an in-vitro model in which stimulated eosinophils released NGF and induced neurite outgrowth, which was abolished by anti-NGF neutralizing antibodies.[33] Besides NGF, brain-derived neurotrophic factor (BDNF) contents are also higher in eosinophils of patients with atopic dermatitis compared with healthy controls and can be released accordingly.[34,35] This is of interest because increased BDNF levels correlate with disease severity assessed by SCORing Atopic Dermatitis score in adults[36] and in children with atopic dermatitis, in which BDNF levels also correlate with scratching activities.[37] Interestingly, scratching behaviour and skin inflammation could be inhibited in a mouse model using the neurotrophin receptor antagonist for tyrosinkinase A receptor.[38]

BDNF also induces chemotaxis of eosinophils in patients with atopic dermatitis, enhancing the recruitment of these proinflammatory cells in the tissue.[35,39] As expression of all neurotrophin receptors is significantly higher in eosinophils of itchy skin diseases such as atopic dermatitis compared with allergic rhinitis and skin healthy controls, the functional capability of neurotrophins may thus be explained by increased receptor expression.[39]

Eosinophils have also been shown to express histamine receptors including the H4 receptor.[40] Furthermore, eosinophils can be a source of neuropeptides such as vascular endothelial growth factor, which might point toward a role in some pruritic skin diseases, possibly including urticaria.[41] Thus, the capability of eosinophils to respond to various trigger factors via the production of neurotrophins, neuropeptides and other cytokines displays a novel pathophysiological aspect in itchy skin diseases.

Novel Itch Mediators: Interleukin-31 and Autotaxin

More recently, a novel cytokine named IL-31 was shown to have a pivotal role in severe itch and chronic dermatitis, as assessed in mice overexpressing IL-31.[42] In Nc/Nga mice, IL-31 levels correlated with scratching behaviour,[43] which could be ameliorated by the use of anti-IL-31 Ab.[44]

In humans, IL-31 levels are increased in itchy skin diseases including chronic urticaria and atopic dermatitis.[45•,46] In atopic dermatitis, levels of IL-31 also correlate with disease severity.[45•,46] IL-31 mRNA has also been shown to be increased in the skin of patients with atopic dermatitis, allergic contact dermatitis and prurigo nodularis.[47] Interestingly, staphylococcal superantigens, which represent a general trigger factor for atopic dermatitis rapidly induced IL-31 mRNA expression in the skin and in peripheral blood mononuclear cells of atopic individuals,[47] which may have an impact on itch sensation (Fig. 1). Cellular sources of IL-31 are represented by skin infiltrating CLA+ T-cells, CD4+ T cells and peripheral blood CD45R0 CLA+ T-cells.[48] Another cellular source of IL-31, which has been identified more recently is dermal mast cells.[27••]

As IL-31 receptors are not only expressed on epithelial cells including keratinocytes but also on dorsal root ganglia (Fig. 1), IL-31 represents an interesting target for the therapy of itch.[47,49]

Recently, autotoxin was identified as a common mediator in different forms of cholestatic pruritus.[50••] Chronic pruritus in cholestatic liver diseases occurs frequently. Kremer et al. [50••] showed in their study that lysophosphatitic acid (LPA) and autotaxin (ATX) are significantly increased in serum levels of patients with cholestatic pruritus. Moreover, serum levels correlated with itch intensity in the patients. Further, intradermal injection of LPA into the skin of mice induced scratching behaviour assuming that LPA and ATX play a pivotal role in cholestatic itch possibly serving as a novel target for future therapeutic interventions.

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