‘Neurotrophology’ of the hair follicle: neurotrophins act as auto‐ and paracrine growth factors and immunomodulators

Neurotrophins are increasingly appreciated as growth factors and immune modulators not only inside but also outside of the nervous system. They are now appreciated to affect a wide variety of epithelial tissues and have become intensely studied in the context of stress‐responses. In mouse skin, for example, the prototypic neurotrophin, nerve growth factor (NGF), is produced by hair follicles and regulates their growth during hair follicle morphogenesis and cycling and the cutaneous responses to psychoemotional stress. Fluctuations in NGF expression are mirrored by changes in nerve fiber density and neuro–immune interactions in hair follicles and interfollicular neural networks. Our recent findings document that, in organ‐cultured human hair follicles, NGF signaling inhibits hair growth (anagen) by the induction of apoptosis‐driven hair follicle regression (catagen). Interestingly, this process appears to depend on stimulation of the pan‐low‐affinity neurotrophin receptor p75, which has recently been identified as a high affinity receptor for the NGF prohormone, proNGF. Moreover, hair follicle regression by neurotrophin signaling may be induced by key stress mediators such as substance P and potentially involves neurogenic inflammation in analogy to the murine model and subsequent collapse of the hair follicle immune privilege. Thus mouse and human hair follicle epithelia are both a prominent peripheral source and a key target for neurotrophins and provide a highly instructive model for dissecting not only general growth‐modulatory activities of NTs in epithelial biology, but also neuro–immune interactions under physiological and pathological conditions.