p75NTR is involved in inflammatory responses in psoriasis

Psoriasis (Pso) is a chronic inflammatory disease of the skin. Toll-like receptors (TLRs) are involved in Pso pathogenesis and their intracellular pathways are activated after the binding with a variety of danger signals such as the alarmins, molecules released from damaged or diseased tissue that stimulate immunomodulatory responses. We recently found that nucle- ophosmin (NPM), a nucleolar protein acts as an alarmin, is released by skin fibroblasts (FBs) and keratinocytes (KCs) upon inflammatory stimuli and increased in Pso patient plasma. The binding of NPM to TLR4 induces NF-kB nuclear translocation and activates inflammatory responses. To find novel interactors in Pso, we focus our study on the NGF receptor p75NTR, whose activation represents a novel inflammatory mechanism. We confirmed that NGF mRNA is increased in Pso-FBs vs healthy donor (HD) FBs. Up-regulation of NGF mRNA can be induced in HD-FBs upon stimulation with a mix of cytokines (MIX) related to Pso. The receptor p75NTR is increased in Pso biopsies vs HD ones and at the mRNA and protein levels in Pso-FBs vs HD-FBs and induced in HD-FBs upon MIX exposure. p75NTR specific inhibitor LM11A-31 (p75i), that blocks proNGF binding to p75NTR, down-regulates MIX-induced inflammatory genes in HD and Pso-FBs by preventing NF-kB nuclear translocation. Proximity ligation assay (PLA) showed that p75NTR interacts with TLR4 and with the alarmin NPM in HD and Pso-FBs upon MIX exposure, and these interactions are abolished by p75i. Moreover, NPM release induced by LPS and MIX treatment is decreased by p75i in Pso-FBs. In conclusion, p75NTR activation is involved in NPM extracellular release and in reinforcing the NPM/TLR4/NF-KB axis activated in Pso inflammatory responses. p75NTR inhibition could be a novel biological target to counteract chronic inflammation associated with Pso.