What causes itch in atopic dermatitis? (original) (raw)
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Mechanisms Regulating Epidermal Innervation in Pruritus of Atopic Dermatitis
Skin Biopsy - Perspectives, 2011
In addition, diminished skin innervation has been observed in the skin of patients with neuropathic itch (Wallengren et al., 2002). This spontaneous itching may emanate from a central nervous system disorder, such as stroke, and continue in partly denervated skin. However, its mechanisms have not yet been elucidated. 3. Regulation of epidermal nerve fiber density by axonal guidance molecules 3.1 Nerve elongation factors Nerve growth factor (NGF) is a neurotrophin that affects neurite outgrowth and neuronal survival (Lewin et al., 1993). Keratinocyte-derived NGF is a major mediator of skin innervation density, with higher local NGF concentrations in the lesional skin of patients with prurigo nodularis, AD, psoriasis, contact dermatitis and xerosis than in normal skin (Ikoma et al., 2006). In adult rat primary sensory neurons, NGF has been shown to upregulate neuropeptides, especially substance P (SP) and calcitonin-gene-related peptide (CGRP) (Verge et al., 1995), both of which are involved in the hypersensitivity of itch sensation and neurogenic inflammation (Steinhoff et al., 2003). Several studies using NC/Nga mice have demonstrated that anti-NGF approaches significantly inhibited both epidermal nerve growth and scratching behavior, but did not ameliorate scratching that had already developed (Takano et al., 2005; Takano et al., 2007). These anti-NGF approaches, however, did not completely inhibit itch responses, indicating that other mechanisms may also regulate epidermal innervation. Amphiregulin (AR), a protein belonging to the epidermal growth factor (EGF) family, has been found to affect nerve fiber elongation (Kimura et al., 1992; Nilsson and Kanje, 2005). AR expression was also shown to be upregulated in the epidermis of NC/Nga mice with AD (Tominaga et al., 2007a), suggesting that AR is a regulator of epidermal nerve density in the skin. Matrix metalloproteinases (MMPs) have been reported to catalyze the release of AR from transmembrane precursors, a release blocked by GM6001, a broad-spectrum MMP inhibitor, and by MMP-2/MMP-9 (i.e. gelatinase A/B) inhibitors (Kansra et al., 2004). Gelatinase activities were found to be higher in the suprabasal layer of atopic NC/Nga mice than in controls (Tominaga et al., 2007a). In addition, transmembrane-type AR was found to localize on the cell surface of basal cells, whereas AR was diffused in the suprabasal layer. Thus, gelatinase in suprabasal cells may be involved in AR elaboration into the intercellular space between keratinocytes. TNF- is a pivotal proinflammatory cytokine in the innate immune response and a key molecule for skin inflammation. Mast cells have been identified as important sources of TNF- (Steinhoff et al., 2003). Plasma TNF- concentration is increased in AD (Sumimoto et al., 1992), and both TNF- and its receptors are upregulated in dermal blood vessels from patients with psoriasis (Kristensen et al., 1993). A study using mast cell-and TNF-deficient mice demonstrated that TNF produced by mast cells promotes the elongation of epidermal and dermal nerve fibers in a mouse model of contact dermatitis (Kakurai et al., 2006). Partly because of their close anatomical association, it has been suggested that cutaneous sensory nerves and mast cells may represent a functional unit, whereby stimulated nerve fibers may activate local mast cells, which in turn can control local nerve function (Steinhoff et al., 2003). Thus, mast cell-derived TNF may act as a nerve elongation factor in inflamed skin. TNF receptors are also expressed on peripheral nerves (Shubayev et al., 2004). TNF may also directly affect sensory nerves, but the details are still uncertain. More recently, TNF- was
An Update on Peripheral Mechanisms and Treatments of Itch
Biological and Pharmaceutical Bulletin, 2013
Histamine H 1-receptor blockers are used to treat all types of itch resulting from serious skin diseases such as atopic dermatitis, as well as from renal and liver diseases. However, they often lack efficacy in chronic itch, a profound clinical problem that decreases quality of life. The development of effective treatments requires a full understanding of the fundamental mechanisms of itch. Recent studies have indicated that the pathogenic mechanisms of itch also involve agonists other than histamine, including proteases, neuropeptides, cytokines, and opioids, as well as their cognate receptors. Release of these pruritogenic mediators and modulators into the periphery may directly activate itch-mediating C-fibers via specific receptors on the nerve terminals. Histological observations have shown increased epidermal nerve densities in patients with atopic dermatitis, suggesting that the higher density is at least partly responsible for itch sensitization. This hyperinnervation is likely induced by an imbalance between nerve elongation and repulsion factors produced by keratinocytes. Neuronal matrix metalloproteinases are also involved in the penetration of nerve fibers into the extracellular matrix. Moreover, itch-mediating fibers such as gastrin-releasing peptide + (GRP +) and Mas-related G-protein coupled receptor A3 + (MrgprA3 +) fibers are present in the skin. Clinically, emollients or UV-based therapies can partly control epidermal nerve density, but new substances and classes of antipruritic drugs are needed. This review highlights recent knowledge regarding epidermal nerve fibers that are partly involved in itch sensitization, and discuss peripheral mechanisms and treatments of itch, especially in atopic dermatitis.
The Pathology of Type 2 Inflammation-Associated Itch in Atopic Dermatitis
Diagnostics, 2021
Accumulated evidence on type 2 inflammation-associated itch in atopic dermatitis has recently been reported. Crosstalk between the immune and nervous systems (neuroimmune interactions) is prominent in atopic dermatitis research, particularly regarding itch and inflammation. A comprehensive understanding of bidirectional neuroimmune interactions will provide insights into the pathogenesis of itch and its treatment. There is currently no agreed cure for itch in atopic dermatitis; however, increasing numbers of novel and targeted biologic agents have potential for its management and are in the advanced stages of clinical trials. In this review, we summarize and discuss advances in our understanding of type 2 inflammation-associated itch and implications for its management and treatment in patients with atopic dermatitis.
Journal of Investigative Dermatology, 2013
Keep up to date with the latest JID research and news! Follow us on: Facebook Twitter Aims and Scope of JournalThe Journal of Investigative Dermatology (JID) publishes high impact reports describing original research related to all aspects of cutaneous biology and skin disease. Descriptions of important findings that result from basic, translational, or clinical research are appropriate for submission. Clinical research can include, but is not limited to, interventional trials, genetics studies, epidemiology, and health services research. For more information, see our Instructions for Authors.
Connections between Immune-Derived Mediators and Sensory Nerves for Itch Sensation
International Journal of Molecular Sciences, 2021
Although histamine is a well-known itch mediator, histamine H1-receptor blockers often lack efficacy in chronic itch. Recent molecular and cellular based studies have shown that non-histaminergic mediators, such as proteases, neuropeptides and cytokines, along with their cognate receptors, are involved in evocation and modulation of itch sensation. Many of these molecules are produced and secreted by immune cells, which act on sensory nerve fibers distributed in the skin to cause itching and sensitization. This understanding of the connections between immune cell-derived mediators and sensory nerve fibers has led to the development of new treatments for itch. This review summarizes current knowledge of immune cell-derived itch mediators and neuronal response mechanisms, and discusses therapeutic agents that target these systems.
Allergy, 2014
Background: The most intriguing function attributed to interleukin-31 (IL-31) is its ability to induce pruritus in pathologic conditions, such as atopic dermatitis (AD). As of today, this feature of IL-31 was tested in vivo only in animal models. Methods: Ten patients with AD and 10 healthy controls were challenged with IL-31 and NaCl (negative control) by skin prick testing. Twenty additional healthy controls were subjected to skin prick testing with histamine. Itch and local inflammatory responses of the skin were assessed for up to 72 h. Results: All of the histamine-challenged subjects developed immediate pruritus (i.e. within the first 5 min). In contrast, only one IL-31-and two of the NaClchallenged subjects reported immediate itch at the provocation site (short lasting, for 2-6 min). Nine subjects (five patients with AD) reported late itch responses to IL-31 challenges with a mean delay of 143 min. No subject reported late itch responses to histamine or NaCl testing. There was no significant difference in IL-31-induced itch start time, duration and intensity between patients with AD and healthy volunteers. Conclusion: IL-31 does not induce immediate itch responses in humans. The late onset of IL-31-induced itch supports the notion that IL-31 exerts its pruritic effect indirectly via keratinocytes and secondary mediators, rather than through its receptors on cutaneous nerves.
Role of SNAREs in Atopic Dermatitis–Related Cytokine Secretion and Skin-Nerve Communication
Journal of Investigative Dermatology, 2019
The role of soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) in atopic dermatitis (AD) is unknown. This study is envisioned to lead to the previously unreported SNARE function in AD-related cytokine secretion and epidermis-nerve communication. Herein, we report that various cytokines were simultaneously upregulated and co-released in the innate immunity-activated primary human keratinocytes (phKCs). AD-related cytokines thymic stromal lymphopoietin (TSLP), endothelin-1 (ET-1) or inflammatory TNF-α activated distinct but overlapping sensory neurons. Interestingly, TNF-α potentiated TSLP-induced Ca 2+-influx, whereas ET-1 caused itch-selective B-type natriuretic peptide (BNP) release. In phKCs, BNP upregulated genes promoting dermatological and neuroinflammatory diseases and conditions. VAMP3, SNAP-29 and syntaxin4 proved important in driving cytokine release from phKCs. Depletion of VAMP3 inhibited nearly all the cytokine release including TSLP and ET-1. Accordingly, VAMP3 co-occurred with ET-1 in AD patient skin. Our study pinpoints the pivotal role of SNAREs in mediating cytokine secretion related to AD. VAMP3 is identified as a suitable target for developing broad-spectrum anti-cytokine therapeutics for controlling itch and atopic skin inflammation.
Intractable Itch in Atopic Dermatitis: Causes and Treatments
Biomedicines
Itch or pruritus is the hallmark of atopic dermatitis and is defined as an unpleasant sensation that evokes the desire to scratch. It is also believed that itch is a signal of danger from various environmental factors or physiological abnormalities. Because histamine is a well-known substance inducing itch, H1-antihistamines are the most frequently used drugs to treat pruritus. However, H1-antihistamines are not fully effective against intractable itch in patients with atopic dermatitis. Given that intractable itch is a clinical problem that markedly decreases quality of life, its treatment in atopic dermatitis is of high importance. Histamine-independent itch may be elicited by various pruritogens, including proteases, cytokines, neuropeptides, lipids, and opioids, and their cognate receptors, such as protease-activated receptors, cytokine receptors, Mas-related G protein-coupled receptors, opioid receptors, and transient receptor potential channels. In addition, cutaneous hyperinn...
British Journal of Dermatology, 2012
Background Itch is the cardinal symptom of atopic dermatitis (AD). b-Endorphin, a neuropeptide, is increased in both AD skin and sera. Interleukin (IL)-31, an itch-relevant cytokine, activates IL-31 receptors in keratinocytes. However, how IL-31 and b-endorphin interact in AD skin remains elusive. Objectives To investigate the mechanistic interaction of IL-31 and b-endorphin in AD. Methods This was a prospective cross-sectional study. We recruited adult patients with AD and controls according to Hanifin’s AD criteria. Serum levels of IL-31 and b-endorphin were measured by enzyme-linked immunosorbent assay. Expressions of IL-31 receptor A (IL-31RA) and b-endorphin in the skin were assessed by immunohistochemistry. Their expression in the skin and blood was compared and correlated in patients with AD and in controls. We also treated primary keratinocytes with IL-31 and measured calcium influx, b-endorphin production and signalling pathways to define their mechanistic interactions. Results b-Endorphin was increased in the supernatant from IL-31-treated keratinocytes. IL-31 receptor activation resulted in calcium influx and STAT3 activation; pretreatment with STAT3 inhibitor stopped the increase of b-endorphin. Notably, either replacement of extracellular calcium or treatment with 2-aminoethoxydiphenyl borate, an inhibitor for the store-operated channel, blocked STAT3 activation. We found higher levels of blood b-endorphin and IL-31, which were significantly correlated, in patients with AD. Moreover, IL-31RA and b-endorphin were increased and colocalized both in AD human skin and TPA-painted mouse skin. Conclusions IL-31 receptor activation in keratinocytes induces calcium influx and STAT3-dependent production of b-endorphin. These results might contribute to an understanding of the regulatory mechanisms underlying peripheral itch.