F5 NGF AND ITS PRECURSOR PRONGF PROMOTE P75 NEUROTROPHIN RECEPTOR-MEDIATED HUMAN HAIR FOLLICLE REGRESSION (CATAGEN)
Peters EMJ1, Hansen MG2, Liezman C1, Overall RW1, Nakamura M3, Hagen E1, Klapp BF1, Arck PC1, Paus R2
1Psychoneuroimmunology, Department of Internal Medicine, Psychosomatics, University-Medicine Charité, Campus Virchow, Humboldt-University of Berlin, Berlin, Germany
2Department of Dermatology, University Hospital Hamburg-Eppendorf, Hamburg, Germany
3Department of Dermatology, Kyoto University, Kyoto, Japan

Nerve growth factor (NGF) and its apoptosis-promoting low-affinity panneurotrophin receptor (p75NTR) are involved in the control of murine hair follicle cycling, and NGF is a key mediator of stress-induced hair growth inhibition in mice. However, it is as yet unknown whether human hair follicle growth is also controlled by signalling through p75NTR and/or the growth-promoting high affinity NGF receptor, tyrosinekinase A (TrkA). Moreover, the NGF precursor proNGF, recently defined as a high-affinity ligand to p75NTR, was found in all commercially available NGF preparations, an issue not addressed in cutaneous neurotrophin signalling to date. Here, we show by qPCR that mRNA for proNGF/NGF, p75NTR and TrkA is transcribed in microdissected anagen hair bulbs of human scalp skin. By immunohistomorphometry and in situ hybridization the strongest expression of NGF and proNGF was detected in terminally differentiating inner root sheath keratinocytes. During spontaneous catagen development of organ-cultured human hair follicles, p75NTR mRNA levels rose, and p75NTR- and proNGF-immunoreactivity increased dramatically in involuting compartments, which were largely devoid of TrkA expression. In the regressing epithelial strand TUNEL+ apoptotic cells showed prominent p75NTR-expression. mRNA levels for transforming growth factor-b2 (TGFb2), a key catagen promoter and marker for catagen induction, increased during catagen development in organ culture. Administration of proNGF/NGF inhibited hair shaft elongation, increased TGFb2 transcription and accelerated catagen development of organ-cultured human hair follicles. This could be antagonized by co-administration of p75NTR-blocking antibodies. Our findings suggest an important role for proNGF/NGF interaction with p75NTR in terminating anagen in human hair follicles. This designates p75NTR antagonists interesting candidates for the management of telogen effluvium.