Mechanisms Regulating Epidermal Innervation in Pruritus of Atopic Dermatitis

Histamine, the best-known pruritogen in humans, is also regarded as an experimental itch-causing substance. Clinically, antihistamines, i.e., H1-receptor blockers, are used to treat all types of itch resulting from renal and liver diseases, as well as from serious skin diseases such as atopic dermatitis. Antihistamines, however, often lack efficacy in patients with chronic itch involving other agonists, including proteases, neuropeptides, cytokines, and opioids, as well as their cognate receptors, including thermoreceptors, PAR-2, and opioid receptors. Release of these pruritogenic mediators and modulators into the periphery may directly activate itch-sensitive C-fibers by binding to specific receptors on the nerve terminals (Ikoma et al., 2006; Paus et al., 2006). Nerve fibers can also be activated by exogenous mechanical, chemical, or biological stimuli, resulting in itch responses (Tominaga and Takamori, 2010). Histological examination has shown increased epidermal nerve densities in patients with atopic dermatitis (AD), suggesting that this higher density may be at least partly responsible for the intense itching in the skin. Such hyperinnervation is probably caused by an imbalance of nerve elongation factors (e.g. nerve growth factor, amphiregulin, and gelatinase) and nerve repulsion factors (e.g. semaphorin 3A and anosmin-1) produced by keratinocytes (Tominaga and Takamori, 2010; Tengara et al., 2010). Using a unique system of culturing rat dorsal root ganglion (DRG) neurons, consisting of Boyden chambers and extracellular matrix (ECM), we recently demonstrated that neuronal matrix metalloproteinase-2 (MMP-2) is involved in the penetration of sensory nerve fibers into basement membrane through modulation by axonal guidance molecules and/or ECM (Tominaga et al., 2009a). Clinically, psoralenUVA (PUVA) therapy may reduce epidermal hyperinnervation in patients with AD by normalizing abnormal Sema3A and NGF expression in the epidermis, decreasing in visual analog scale (VAS) scores of pruritus severity (Tominaga et al., 2009c). Such anti-nerve growth effects have been observed in the dry skin of acetone-treated mice following exposure to narrowband-UVB and excimer lamps (Kamo et al., 2011a). These findings may help understand the mechanisms by which UV-based therapy modulate epidermal innervation. This chapter presents recent knowledge regarding the relationship between pruritus and epidermal nerve density, especially in AD.