Nerve growth factor receptor p75NTR interacts with Toll-like receptor 4 and the alarmins high mobility group box 1 and nucleophosmin: a novel inflammatory mechanism in psoriasis

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BACKGROUND: Nerve growth factor (NGF) is upregulated in psoriatic skin, and increasing evidence indicates that its receptor, p75 neurotrophin receptor (p75NTR), promotes inflammatory responses. However, the contribution of p75NTR and its ligand, pro-nerve growth factor (proNGF), in psoriasis inflammation remains unclear. OBJECTIVES: To investigate the role of p75NTR in the inflammatory response of skin fibroblasts derived from plaques from patients with psoriasis, to unravel possible novel interactions. METHODS: Plasma levels of proNGF and p75NTR extracellular domain (ECD) were measured in 54 patients with psoriasis and 25 healthy donors (HDs). p75NTR and tropomyosin receptor kinase A expression were evaluated in skin biopsies and dermal fibroblasts from patients with psoriasis and from HDs. Protein–protein interaction (PPI) analysis was used to prioritize potential p75NTR interactors. The effects of cytokines related to psoriasis [interferon (IFN)-γ, tumour necrosis factor (TNF)-α, interleukin (IL)-22, IL-17A] on receptor expression were examined in skin biopsies and fibroblasts. Pharmacological inhibition of p75NTR with LM11A-31 (p75i) or RNA interference was used to assess effects on intracellular signalling, inflammatory gene expression (IL6, PTGS2, CCL2, CCL20) and molecular interactions using reverse transcription quantitative polymerase chain reaction, Western blotting, enzyme-linked immunosorbent assay and proximity ligation assay (PLA). RESULTS: p75NTR expression was increased in the dermal layer of skin biopsies from psoriasis plaques, and plasma levels of p75NTR ECD and proNGF were enhanced in patients with psoriasis and correlated with disease severity. Psoriasis fibroblasts showed high basal p75NTR expression, which was inducible by the cytokine mix (IFN-γ, TNF-α, IL-22, IL-17A) in HD fibroblasts and blocked by LM11A-31. In fibroblasts from HDs and from patients with psoriasis, p75NTR inhibition significantly reduced cytokine-induced inflammatory gene expression and prevented nuclear translocation of nuclear factor-κB. Similar effects were seen after inhibition of Toll-like receptor 4 (TLR4). PPI analysis identified the alarmins high mobility group box 1 (HMGB1) and nucleophosmin as potential connectors between p75NTR and TLR4. These interactions were confirmed by PLA. Treatment with the cytokine mix enhanced p75NTR–TLR4–alarmin interactions, which were prevented by the p75i. Moreover, nucleophosmin and HMGB1 inhibition decreased p75NTR–TLR4 interaction and inflammatory gene expression. In psoriasis fibroblasts, p75NTR inhibition consistently reduced cytokine mix or lipopolysaccharide-induced extracellular release of nucleophosmin and HMGB1. CONCLUSION: p75NTR upregulation and signalling contribute to alarmin release and amplification of the TLR4–NF-κB inflammatory pathway in psoriasis. p75NTR can be considered a sensor of inflammation required for full activation of TLR4-dependent inflammatory signalling. Thus, p75NTR targeting may represent a novel therapeutic strategy to counteract chronic inflammation in psoriasis.

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