POS0300 SEMAPHORIN5A IS ELEVATED IN PATIENTS WITH PSORIATIC ARTHRITIS AND REINFORCES THE MACROPHAGES EXPRESSION OF KEY PRO-INFLAMMATORY MEDIATORS
Authors: J. Marty Lobo, C. Rafael-Vidal, S. Martínez-Ramos, B. Malvar-Fernández, C. Mouriño, N. Pérez, S. García Pérez, F. J. Maceiras Pan, J. M. Pego-Reigosa, S. García
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> Semaphorin5A (Sema5A), which belongs to Semaphorin protein family, is elevated in patients with rheumatoid arthritis, both at local and systemic levels.[1-3] In these patients, Sema5A plays a role in the activation and differentiation of T helper (Th)1, Th17 and natural killer (NK) cells, inducing the expression of pro-inflammatory cytokines.[2] Moreover, Sema5A also promotes an invasive, pro-inflammatory phenotype in synovial fibroblasts.[3] <h3>Objectives:</h3> To determine whether the expression of Sema5A is also dysregulated in patients with psoriatic arthritis (PsA) and analyze the effect of Sema5A on monocyte-derived macrophages from patients with PsA. <h3>Methods:</h3> Membrane Sema5A expression was determined by flow cytometry in peripheral blood mononuclear cells (PBMCs) from healthy controls (HC) and patients with PsA. Monocytes from patients were isolated from PBMCs and then stimulated with Sema5A (200 ng/mL), LPS (10 ng/mL) or their combination for 4h and 24h. Alternatively, monocytes were differentiated into macrophages in the presence of M-CSF (25 ng/mL). At day 7, macrophages were stimulated during 4h and 24h with Sema5A (200 ng/mL), TNF-α (10 ng/mL) or their combination. Finally, the expression of inflammatory mediators was determined by quantitative PCR (qPCR). <h3>Results:</h3> Sema5A<sup>+</sup> CD4<sup>+</sup> T cells and Sema5A<sup>+</sup> non classical monocytes from patients with PsA were significantly elevated as compared to HC (<i>p</i>&lt;0.05) (Figure 1). Sema5A<sup>+</sup> CD8<sup>+</sup> T cells were also increased in PsA patients as compared to HC, but differences were not significant (<i>p</i>=0.06). We next analyzed the functional consequences of Sema5A stimulation on monocytes and macrophages. Sema5A did not modulate the monocyte expression of inflammatory mediators. On macrophages, Sema5A alone modestly induced the expression of <i>TNF</i>, <i>IL12B</i> and <i>IL23</i>, and enhanced the expression of <i>IL1B</i>, <i>IL6</i>, <i>IL8</i> and <i>TNF</i> induced by TNF-α (Figure 2). <h3>Conclusion:</h3> Our data demonstrate that Sema5A expression is elevated in patients with Sema5A and that, in an inflammatory context, it reinforces the production of inflammatory mediators by macrophages. These results suggest that Sema5A is involved in inflammatory processes observed in the PsA pathogenesis and might be a potential therapeutic target in the treatment of this disease. <h3>REFERENCES:</h3> [1] Xiao, C., Lv, C., Sun, S., Zhao, H., Ling, H., Li, M., Qin, Y., Zhang, J., Wang, J., Yang, X. (2021). TSP1 is the essential domain of SEMA5A involved in pannus formation in rheumatoid arthritis. <i>Rheumatology</i>, 60(12), 5833–5842. [2] Gras, C., Eiz-Vesper, B., Jaimes, Y., Immenschuh, S., Jacobs, R., Witte, T., Blasczyk, R., Figueiredo, C. (2014). Secreted Semaphorin 5A Activates Immune Effector Cells and Is a Biomarker for Rheumatoid Arthritis. <i>Arthritis &amp; Rheumatology</i>, 66(6), 1461–1471. [3] Cheng, Q., Chen, M., Liu, M., Chen, X., Zhu, L., Xu, J., Xue, J., Wu, H., Du, Y. (2022). Semaphorin 5A suppresses ferroptosis through activation of PI3K-AKT-mTOR signaling in rheumatoid arthritis. <i>Cell Death and Disease,</i> 13(7), 1-10. <h3>Acknowledgements:</h3> <b>NIL.</b> <h3>Disclosure of Interests:</h3> <b>None declared.</b>