p75 Neurotrophin Receptor in the Skin: Beyond Its Neurotrophic Function

p75 neurotrophin receptor (p75^NTR), also known as CD271, is the low-affinity receptor that, together with the tyrosine kinase receptor tropomyosin-receptor kinase (Trk), mediate neurotrophin (NT) functions. Beside their classic role in skin innervation, NT and their receptors constitute a complex cutaneous network associated with a number of autocrine and paracrine activities. In this context, the role of p75^NTR is becoming more and more important. This review will focus on the intriguing functions of p75^NTR in healthy and diseased skin. First, p75^NTR counterbalances the proliferative and survival activities of its cognate receptor Trk by inducing keratinocyte apoptosis. In addition, p75^NTR identifies an early transit-amplifying (TA) keratinocyte population and plays a critical role in keratinocyte stem cell transition to its progeny as well as in epidermal differentiation. p75^NTR is absent in psoriatic TA cells, thus rendering these cells resistant to apoptosis. On the other hand, p75^NTR infection restores NT-induced apoptosis in psoriatic keratinocytes. Taken together, these results provide evidence for a critical role of p75^NTR in epidermal homeostasis, while its lack may account for the TA defect in psoriasis. While the issue of p75^NTR as a marker of melanoma initiating cells is still to be solved, there is strong evidence that downregulation of this receptor is a precondition to melanoma invasion and metastasis in vitro and in vivo. All in all, this review points to p75^NTR as a major actor in both physiologic and pathologic conditions at the skin level.