Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Neuroimmune interactions in allergic skin diseases Ferda Cevikbas a , Antje Steinhoff a , Bernhard Homey b and Martin Steinhoff a Purpose of review Recent studies have advanced our understanding that allergic inflammation triggers neuronal dysfunction, thereby modulating inflammation-related changes in affected tissues including the skin. Vice versa, evidence has emerged that inflammatory responses are controlled by neurons. Moreover, structural cells and invading immune cells express neuronal receptors and release mediators which directly communicate with nerve endings in the skin. Recent findings During the allergic response, skin cells do not only represent a significant source of neuromediators but also represent targets for neuropeptides or neurotrophins as well as neurotransmitters in the inflamed tissue. During the last decade, it has become obvious that a large variety of molecules influence the adaptive as well as the innate immune response. Beside neuropeptide receptors, proteinase-activated receptors, novel histamine receptors, different cytokine or chemokine receptors play a role in the pathophysiology of atopic and allergic diseases. Summary Peripheral sensory and autonomic nerves are critically involved in many pathways of the innate and adoptive immune system during allergic and atopic skin diseases. Further dissection of receptor-mediated and intracellular signal pathways will help to develop more effective therapeutic approaches for allergic and inflammatory skin diseases. Keywords allergy, neuroimmunology, neuromediator, proteinase- activated receptor Curr Opin Allergy Clin Immunol 7:365 –373. ß 2007 Lippincott Williams & Wilkins. a Department of Dermatology, IZKF Moenster and Boltzmann-Institute for Cell and Immunobiology of the Skin, University of Mu ¨ nster, Germany and b Department of Dermatology, University of Du ¨ sseldorf, Germany Correspondence to Martin Steinhoff, MD, PhD, Department of Dermatology, IZKF Moenster and Boltzmann-Institute for Cell and Immunobiology of the Skin, University of Mu ¨ nster, Von-Esmarch Str. 58, 48149 Mu ¨ nster, Germany E-mail: msteinho@uni-muenster.de Current Opinion in Allergy and Clinical Immunology 2007, 7:365–373 Abbreviations a-MSH a-melanocyte stimulating hormone BDNF brain derived neurotrophic factor CGRP calcitonin gene-related peptide CHS contact hypersensitivity NGF nerve growth factor PAR protease-activated receptor TNF-a tumor necrosis factor a TRPV transient receptor potential vanilloid VIP vasoactive intestinal peptide ß 2007 Lippincott Williams & Wilkins 1528-4050 Introduction Understanding the complex pathophysiology of allergic diseases has become a main challenge of clinical and experimental research. Recent evidence indicates that cutaneous allergic and atopic inflammatory processes are influenced by neuronal mediators released directly from neurons or structural cells. In general, allergic diseases of the skin are mediated by the innate and adaptive immune system which, in turn, induces the production of immuno- globulin E (IgE) antibodies (type I hypersensitivity) or T-cell-derived mediators (type IV hypersensitivity). Whether neuromediators play a role in the regulation of immune complex mechanisms (type III hypersensitivity) is unknown. It has become obvious that neurons and activated struc- tural cells such as keratinocytes, endothelial cells, fibro- blasts, epidermal dendritic and Langerhans cells, for example, are capable of releasing neuromediators into the site of inflammation, thereby modulating the immune response. For instance, neurotrophins such as nerve growth factor (NGF) or neurotrophin-4 (NT-4) are well known to mediate inflammatory signals [1  –3  ], and show increased levels in patients with atopic dermatitis and psoriasis [4]. Furthermore, the density of neuropeptide- positive nerve fibers is increased in lesions of patients suffering from atopic dermatitis. These results indicate that neurotrophins act on sensory nerves, leading to enhanced nerve sprouting and sensitization. Moreover, enhanced levels of neuropeptides released from nerve endings or resident and immune cells influence the exacer- bation of allergic skin diseases such as atopic or allergic contact dermatitis. This review highlights the current concept of a cutaneous neuroimmune network and focuses on recent research projects [1  –3  ,5  ,6  ,7,8  ,9] and inno- vative therapeutic options. 365