Substance P as an Immunomodulatory Neuropeptide in a Mouse Model for Autoimmune Hair Loss (Alopecia Areata)

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.

Involvement of Substance P and the Neurokinin-1 Receptor in Radiation-Induced Hair Loss in Mice

“…Previous reports have demonstrated that hair loss was induced by substance P (SP), a product of preprotachykinin-A (PPT-A) mRNA, and its receptor, neurokinin-1 receptor (NK 1 R) (7), and that no hair loss was observed in the skin of NK 1 R-knockout mice (8). From the finding mentioned above, we hypothesized that SP and NK 1 R are involved in radiation dermatitis.…”

Stress Hormone and Skin Disease

“…SP plays an important role in catagen development. It causes MHC-class I based IP to collapse (Peters et al, 2007). The number of SP-immunoreactive nerve fibers increase during early stage of AA, and decrease during advanced stage.…”

“…The number of SP-immunoreactive nerve fibers increase during early stage of AA, and decrease during advanced stage. SP and SP-degrading enzymes are highly expressed in the skin of AA-affected humans (Toyoda et al, 2001) and in the C3H/HeJ mouse model (Siebenhaar et al, 2007). AA onset may require stress-induced SP expression in the skin (Peters et al, 2006(Peters et al, , 2007.…”

“…SP facilitates catagen development by promotion of mast cell degranulation and also induces a loss of IP markers in HFs (Arck et al, 2001;Peters et al, 2007).…”

Molecular Basis of Neuroimmune Interaction in an In Vitro Coculture Approach

“…Acute restraint stress resulted dura mater mast cell activation in normal mice but not in NK-1 receptor-knockout mice (118). Substance P and NK-1 receptors are also reported to act as important regulators in the molecular signaling network modulating inflammatory response in alopecia areata and autoimmune hair loss (119)(120)(121).…”