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(American Journal of Pathology. 2006;169:1713-1721.)
© 2006 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2006.060602

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

Maki Kakurai^*, Rossella Monteforte^*, Hajime Suto^*, Mindy Tsai^*, Susumu Nakae^* and Stephen J. Galli^*

From the Departments of Pathology^* and Microbiology and Immunology, Stanford University School of Medicine, Stanford, California; and the Atopy Research Center, Juntendo University, Tokyo, Japan

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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