1. ¹Departments of Dermatology, Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, Massachusetts, USA
2. ²Department of Dermatology and Allergy, University Medicine-Charité, Humboldt University of Berlin, Berlin, Germany
3. ³Department of Internal Medicine, Psychoneuroimmunology, University Medicine-Charité, Humboldt University of Berlin, Berlin, Germany
4. ⁴Department of Dermatology, Philipp University Marburg, Marburg, Germany
5. ⁵The Jackson Laboratory, Bar-Harbor, Maine, USA
6. ⁶Laboratory of Skin Development, Regeneration and Carcinogenesis, Medical Biosciences, School of Life Science, University of Bradford, Bradford, UK

Correspondence: Dr Vladimir A. Botchkarev, Department of Dermatology, Boston University School of Medicine, 609 Albany Street, Boston, Massachusetts 02118, USA. E-mail: vladbotc@bu.edu

Received 6 November 2005; Revised 23 August 2006; Accepted 5 October 2006; Published online 1 February 2007.

Abstract

Alopecia areata (AA) is an autoimmune disorder of the hair follicle characterized by inflammatory cell infiltrates around actively growing (anagen) hair follicles. Substance P (SP) plays a critical role in the cutaneous neuroimmune network and influences immune cell functions through the neurokinin-1 receptor (NK-1R). To better understand the role of SP as an immunomodulatory neuropeptide in AA, we studied its expression and effects on immune cells in a C3H/HeJ mouse model for AA. During early stages of AA development, the number of SP–immunoreactive nerve fibers in skin is increased, compared to non-affected mice. However, during advanced stages of AA, the number of SP-immunoreactive nerves and SP protein levels in skin are decreased, whereas the expression of the SP-degrading enzyme neutral endopeptidase (NEP) is increased, compared to control skin. In AA, NK-1R is expressed on CD8+ lymphocytes and macrophages accumulating around affected hair follicles. Additional SP supply to the skin of AA-affected mice leads to a significant increase of mast cell degranulation and to accelerated hair follicle regression (catagen), accompanied by an increase of CD8+ cells-expressing granzyme B. These data suggest that SP, NEP, and NK-1R serve as important regulators in the molecular signaling network modulating inflammatory response in autoimmune hair loss.