Increase in NGF content and nerve fiber sprouting in human allergic contact eczema

Kinkelin, Ilka; Mötzing, S; Koltenzenburg, M; Bröcker, Eva‐B.

doi:10.1007/s004410000202

Cited by 99 publications

(88 citation statements)

References 44 publications

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“…Sensitization of itch-signaling pathways has been proposed as a critical mechanism underlying chronic itch (41,42). In ACD and atopic dermatitis, nerve fiber densities are increased in the epidermis (43,44). Extension of these nerve fibers into the epidermis may contribute to spontaneous itch, aggravating itch responses and sensitization of itch signaling pathways (42).…”

Section: Discussionmentioning

confidence: 99%

IL-33/ST2 signaling excites sensory neurons and mediates itch response in a mouse model of poison ivy contact allergy

Liu

Tai

Achanta

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

223

195

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Poison ivy-induced allergic contact dermatitis (ACD) is the most common environmental allergic condition in the United States. Case numbers of poison ivy ACD are increasing due to growing biomass and geographical expansion of poison ivy and increasing content of the allergen, urushiol, likely attributable to rising atmospheric CO 2 . Severe and treatment-resistant itch is the major complaint of affected patients. However, because of limited clinical data and poorly characterized models, the pruritic mechanisms in poison ivy ACD remain unknown. Here, we aim to identify the mechanisms of itch in a mouse model of poison ivy ACD by transcriptomics, neuronal imaging, and behavioral analysis. Using transcriptome microarray analysis, we identified IL-33 as a key cytokine up-regulated in the inflamed skin of urushiol-challenged mice. We further found that the IL-33 receptor, ST2, is expressed in small to medium-sized dorsal root ganglion (DRG) neurons, including neurons that innervate the skin. IL-33 induces Ca 2+ influx into a subset of DRG neurons through neuronal ST2. Neutralizing antibodies against IL-33 or ST2 reduced scratching behavior and skin inflammation in urushiol-challenged mice. Injection of IL-33 into urushiol-challenged skin rapidly exacerbated itch-related scratching via ST2, in a histamine-independent manner. Targeted silencing of neuronal ST2 expression by intrathecal ST2 siRNA delivery significantly attenuated pruritic responses caused by urushiol-induced ACD. These results indicate that IL-33/ST2 signaling is functionally present in primary sensory neurons and contributes to pruritus in poison ivy ACD. Blocking IL-33/ST2 signaling may represent a therapeutic approach to ameliorate itch and skin inflammation related to poison ivy ACD.A llergic contact dermatitis (ACD) is a common allergic skin condition caused by environmental or occupational allergens (1). In the United States, the most common cause of ACD is contact with poison ivy, which affects >10 million Americans per year (2, 3). Poison ivy ACD is also a serious occupational hazard, particularly among firefighters, forestry workers, and farmers, accounting for 10% of total U.S. Forest Services losttime injuries, and it often torments outdoor enthusiasts as well (3, 4). The major allergen in poison ivy is urushiol, contained in the oleoresinous sap of the plant and of related plants (e.g., poison oak and poison sumac) (5). An estimated 50-75% of Americans are sensitized to urushiol (6). Elevated atmospheric carbon dioxide and warming temperatures have increased the biomass of poison ivy and related plants, widened their geographic distribution, and increased plant urushiol content (7). These factors will likely increase allergenicity and result in even larger case numbers of poison ivy ACD in the future (8).The clinical manifestations of poison ivy-induced ACD are intense and persistent itch (pruritus), burning sensation, skin rashes, and swelling, followed by the appearance of vesicles in severe cases (2, 3, 9). Skin inflammation and pruritus ...

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Section: Discussionmentioning

confidence: 99%

IL-33/ST2 signaling excites sensory neurons and mediates itch response in a mouse model of poison ivy contact allergy

Liu

Tai

Achanta

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

223

195

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“…The rostral back skin was weighed and stored at −80°C until the assay. A summary of the procedure for extracting NGF from the skin was previously given (22). The tissue was homogenized in an extraction buffer containing 0.4 M NaCl, 0.5% bovine serum albumin, 10 mM EDTA (Wako, Osaka), 0.05% Tween (Kanto Kagaku, Tokyo), 20 µL / mL aprotinin, 0.1 mM benzethonium chloride, and 0.1% phenylmethylsulfonylfluoride (Sigma) in phosphate buffer.…”

Section: Methodsmentioning

confidence: 99%

Effects of Anti-Nerve Growth Factor Antibody on Symptoms in the NC/Nga Mouse, an Atopic Dermatitis Model

2005

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Abstract. Nerve growth factor (NGF) is an important substance in the skin, where it can modulate nerve maintenance and repair. However, the direct link between NGF and pruritic disease such as atopic dermatitis is not yet fully understood. To determine whether NGF plays a major role in atopic dermatitis and in the development or maintenance of skin lesions, we performed a study using NC / Nga mice and compared mice with and without skin lesions. Our examinations of the NC / Nga mice sought to detect nerve fibers in the epidermis, measured serum and skin NGF content, and observed skin NGF by immunohistochemistry staining. We also examined the effects of anti-NGF antibody on dermatitis symptoms in NC / Nga mice. In these mice, nerve fibers were significantly increased in the epidermis of lesioned skin, and the NGF content of the serum and skin was significantly elevated. Anti-NGF antibodies significantly inhibited the development and proliferation of skin lesions and epidermal innervation and significantly inhibited any growth in scratching but did not ameliorate scratching already developed. Our findings suggest that NGF plays important roles in the pathogenesis of atopic dermatitis-like skin lesions and that inhibiting the physiological effects of NGF or suppressing increased NGF production may prevent or even moderate the symptoms of atopic dermatitis.

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“…First, as noted above, the length of epidermal nerve fibers can be significantly increased in patients with contact eczema 8 or AD, 9 disorders in which mast cells have been implicated. Second, mast cells also are required for optimal expression of certain models of CHS in mice.…”

mentioning

confidence: 93%

“…6 In addition, it has recently been reported that increases in sensory nerve fibers occur in both the epidermis and the dermis in a model of CHS in mice. 7 Moreover, in humans, the length of epidermal nerve fibers can be significantly increased in patients with contact eczema 8 or AD, 9 and increases in both dermal and epidermal nerve fibers have been reported in other dermatological conditions as well, such as prurigo nodularis 10 and notalgia paraesthetica.…”

mentioning

confidence: 97%

Mast Cell-Derived Tumor Necrosis Factor Can Promote Nerve Fiber Elongation in the Skin during Contact Hypersensitivity in Mice

Kakurai

Monteforte

Suto

et al. 2006

The American Journal of Pathology

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In humans, lesions of contact eczema or atopic dermatitis can exhibit increases in epidermal nerves, but the mechanism resulting in such nerve elongation are not fully understood. We found that contact hypersensitivity reactions to oxazolone in mice were associated with significant increases in the length of nerves in the epidermis and dermis. Using genetically mast cell-deficient c-kit mutant mice selectively repaired of their dermal mast cell deficiency with either wild-type or tumor necrosis factor (TNF)-deficient mast cells, we found that mast cells, and mast cell-derived TNF, significantly contributed to the elongation of epidermal and dermal PGP 9.5 ؉ nerves and dermal CGRP ؉ nerves, as well as to the inflammation observed at sites of contact hypersensitivity in response to oxazolone. Moreover, the percentage of mast cells in close proximity to dermal PGP 9.5 ؉ nerve fibers was significantly higher in wild-type mice and in c-kit mutant mice repaired of their dermal mast cell deficiency by the adoptive transfer of wild-type mast cells than in TNF-deficient mice or in TNF ؊/؊ mast cell-engrafted c-kit mutant mice. These observations show that mast cells, and mast cell-derived TNF, can promote the elongation of cutaneous nerve fibers during contact hypersensitivity in the mouse.

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Increase in NGF content and nerve fiber sprouting in human allergic contact eczema

Cited by 99 publications

References 44 publications

IL-33/ST2 signaling excites sensory neurons and mediates itch response in a mouse model of poison ivy contact allergy

IL-33/ST2 signaling excites sensory neurons and mediates itch response in a mouse model of poison ivy contact allergy

Effects of Anti-Nerve Growth Factor Antibody on Symptoms in the NC/Nga Mouse, an Atopic Dermatitis Model

Mast Cell-Derived Tumor Necrosis Factor Can Promote Nerve Fiber Elongation in the Skin during Contact Hypersensitivity in Mice

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