p75NTR is involved in inflammatory responses in psoriasis

Background. Psoriasis is a cutaneous chronic inflammatory disease, characterized by excessive proliferation and abnormal differentiation of keratinocytes and infiltration of multiple inflammatory cells. Moreover, different neuropeptides have been involved in the pathogenesis of psoriasis. NGF is known to increase in psoriasis and to cause neuropeptides increase in keratinocytes (1). We previously showed that the nucleolar protein nucleophosmin (NPM) is actively released by skin fibroblasts and keratinocytes upon cytokine mix related to psoriasis and is also increased in plasma of Pso patients (2). NPM acts as an alarmin eliciting inflammation via nuclear factor kappa B (NF-kB) transcriptional activation (2,3). The role of nerve growth factor (NGF) and its receptors is poorly investigated in psoriasis. Methods. 29 Pso were compared to 25 control subjects (Ctrl) age- and sex-matched. All Pso had a severe psoriasis, defined as Psoriasis Area and Severity Index (PASI) > 10 and one of the following: at least two systemic psoriasis treatments, psoriasis onset < 40 years of age, disease duration >10 years. Exclusion criteria were: diabetes, cerebrovascular events, myocardial infarction, and/or myocardial revascularization, psoriatic arthritis. HD and Pso Fbs were extracted by skin biopsies. Results Our results show that NGF mRNA is increased in Pso fibroblasts (FBs) vs healthy donor (HD) FBs and in HD FBs upon cytokine mix related to psoriasis (MIX) exposure. p75NTR is increased in Pso biopsies vs HD ones and in FBs of Pso patients at the mRNA levels and protein level, and is increased in HD FBs upon cytokine exposure. TrkA is induced at the mRNA level upon MIX exposure. The ratio of TrkA/p75NTR is higher in HD FBs at basal and upon MIX exposure compared to Pso FBs. Moreover, soluble p75NTR and proNGF are up-regulated in plasma of 29 Pso compared to 25 HD controls. The specific p75NTR inhibitor (LM11A-31) decreased LPS and cytokine MIX treatment-induced inflammatory genes (IL-6 and COX-) up-regulation in Pso FBs. In keeping, LM11A-31 prevents NF-kB p65 nuclear translocation in HD FBs upon MIX. Finally, p75NTR interacts with Toll like receptor (TLR) 4 and the alarmin Nucleophosmin (NPM), and this interaction is decreased by LM11A-31. Interestingly, NPM extracellular release induced by Il-1b, LPS and MIX treatment is decreased by LM11A-31 in HD FBs. Conclusion p75NTR/proNGF molecular pathway seems to be involved in the extracellular release of NPM and to reinforce the NPM/TLR4/NF-KB axis activation involved in Psoriasis. p75NTR inhibition could be a novel biological target to counteract chronic inflammation associated with Pso.