p75 Neurotrophin Receptor in the Skin: Beyond Its Neurotrophic Function

Carlo Pincelli

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.