p75 neurotrophin receptor mediates apoptosis in transit amplifying cells and its overexpression restores cell death in psoriatic keratinocytes

Carlo Pincelli (1) , Francesca Truzzi (1) , Alessandra Marconi (1) , Paola Atzei (1) , Maria Cristina Panza (1) , Roberta Lotti (1) , Katiuscia Dallaglio (1) , Rossana Tiberio (1) , Elisabetta Palazzo (1) , Cristina Vaschieri (1)

1 Dermatology

p75 neurotrophin receptor (p75NTR) belongs to the TNF-receptor superfamily and signals apoptosis in many cell settings. In human epidermis, p75NTR is mostly confined to the transit amplifying (TA) subpopulation of basal keratinocytes. Brain-derived neurotrophic factor (BDNF) or neurotrophin-4 (NT-4), that signal through p75NTR, induce keratinocyte apoptosis, while β-amyloid, a ligand for p75NTR, triggers caspase-3 activation to a greater extent in p75NTR transfected cells. Moreover, p75NTR co-immunoprecipitates with NRAGE, induces the phosphorylation of c-Jun N-terminal kinase (JNK) and reduces nuclear factor kappa B (NF-κB) DNA binding activity. p75NTR also mediates pro-NGF-induced keratinocyte apoptosis through its co-receptor sortilin. Furthermore, BDNF or β-amyloid cause cell death in TA, but not in keratinocyte stem cells (KSC) or in p75NTR silenced TA cells. p75NTR is absent in lesional psoriatic skin and p75NTR levels are significantly lower in psoriatic than in normal TA keratinocytes. The rate of apoptosis in psoriatic TA cells is significantly lower than in normal TA cells. BDNF or β-amyloid fail to induced apoptosis in psoriatic TA cells, and p75NTR retroviral infection restores BDNF- or β-amyloid-induced apoptosis in psoriatic keratinocytes. These results demonstrate that p75NTR plays a proapoptotic role in keratinocytes, and is involved in the maintenance of epidermal homeostasis.

Mots clés: p75NTR; keratinocyte; apoptosis; psoriasis

Carlo Pincelli, Francesca Truzzi, Alessandra Marconi, Paola Atzei, Maria Cristina Panza, et al.. p75 neurotrophin receptor mediates apoptosis in transit amplifying cells and its overexpression restores cell death in psoriatic keratinocytes. Cell Death and Differentiation, 2010, ⟨10.1038/cdd.2010.162⟩. ⟨hal-00599476⟩