Enhanced NRP1 Expression in Dendritic Cells of Systemic Lupus Erythematosus and Its Impact on T Cell Proliferation

Abstract

Abstract Background Neuropilin-1 (NRP1) is a transmembrane glycoprotein that acts as a receptor of class III/IV semaphorins known to play a role in the pathogenesis of autoimmune diseases. To date there has been only limited research into the role NRP1 plays in autoimmune inflammatory rheumatic diseases, including systemic lupus erythematosus (SLE). This study aimed to investigate the clinical and pathogenetic roles of NRP1 expression in lupus mouse models and patients with SLE. Methods NRP1 expression was measured by flow cytometry, polymerase chain reaction (PCR), and immunofluorescence assay using peripheral blood mononuclear cells (PBMCs) taken from both healthy controls and patients with SLE, as well as dendritic cells and renal tissues of both control mice and TLR-7 agonist-induced lupus mice. The correlation between NRP1 expression in PBMCs and disease activity markers were analyzed in patients with SLE (n = 57). To determine the effects of NRP1 on dendritic cells on T cells, as well as their mechanism, a proliferation assay was performed by flow cytometry, and the underlying signaling, including the MAPKs and NF-κB pathway, were examined with immunoblotting. Results The expression of NRP1 in dendritic cells and the kidneys was significantly higher in the lupus murine group than in the control group. The dendritic cells in the patients with SLE also showed a markedly higher expression of NRP1 than those of the healthy controls. The correlation analysis showed a significant positive relationship between NRP1 expression and disease activity markers, which included SLEDAI-2K score, as well as C3, C4 and anti-dsDNA antibody titers. The NRP1 antagonist (EG00229) decreased the capacity of dendritic cells on the proliferation of T cells under the condition of TLR7 agonist stimulation. It also downregulated the phosphorylation of ERK1/2 and NF-κB in dendritic cells. Conclusion Our results show that NRP1 is highly expressed in the dendritic cells of SLE patients, and its expression is significantly correlated with known disease activity markers. The inhibition of NRP1 in dendritic cells diminishes the proliferation of T cells, an effect that is mediated by the suppression of MAPKs and NF-kB signaling. These results indicate that dendritic cells with enhanced NRP1 expression alter immune functions by increasing T cell proliferation as part of the pathogenesis of SLE; accordingly, NRP1 may be a potential target in the search for a treatment for SLE.