Frontiers in immunology · 2026
Gene expression profiling of dendritic cell tolerance dysfunction in women with systemic lupus erythematosus.
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Hernández-Ledesma Ana Laura, Coss-Navarrete Evelia Lorena, Salazar-Magaña Sofia, Ramírez-Espinosa Diego, Tinajero-Nieto Lizbet, Torres-Valdez Estefania, Peña-Ayala Angélica H, Félix-Rodriguez Guillermo, Frontana-Vázquez Gabriel, García Sotelo Jair Santiago, Thomas-Chollier Morgane, Trynka Gosia, Rosetti Florencia, Fernandez-Valverde Selene L, Gutiérrez-Arcelus María, Alpízar-Rodríguez Deshiré, Medina-Rivera Alejandra
Аннотация
BACKGROUND: Dendritic cells (DCs) are central regulators of immune tolerance, and disturbances in their phenotype and function contribute to the breakdown of self-tolerance in systemic lupus erythematosus (SLE). Tolerogenic DCs (tolDCs), which suppress autoreactive responses and promote peripheral tolerance, are a promising therapeutic focus in autoimmune diseases.
METHODS: Here, we analyzed the transcriptional profiles of in vitro generated DCs derived from monocytes of individuals with SLE and healthy controls to identify disease-specific disruptions in tolerance associated pathways.
RESULTS: Interferon stimulated genes (ISGs) emerged as dominant markers across all cellular contexts, with monocytes exhibiting the most substantial enrichment; key ISGs (IFI27, IFI44L, USP18, IFI6) acted as central hubs in regulatory networks, underscoring their diagnostic and pathogenic significance. In tolDCs from SLE donors, lipid metabolism pathways were selectively altered, suggesting impaired synthesis of pro-resolving lipid mediators. Additionally, diminished IL10RA expression and dysregulated IRF4 activity in SLE moDCs indicated intrinsic defects in IL-10 mediated tolerogenic differentiation.
CONCLUSION: Together, these findings suggest that interferon driven transcriptional rewiring, impaired IL-10 signaling, and aberrant lipid metabolic programming converge to compromise DCs tolerogenic capacity in SLE. This highlights key mechanistic pathways that could be targeted to restore immune tolerance and reduce chronic inflammation.
METHODS: Here, we analyzed the transcriptional profiles of in vitro generated DCs derived from monocytes of individuals with SLE and healthy controls to identify disease-specific disruptions in tolerance associated pathways.
RESULTS: Interferon stimulated genes (ISGs) emerged as dominant markers across all cellular contexts, with monocytes exhibiting the most substantial enrichment; key ISGs (IFI27, IFI44L, USP18, IFI6) acted as central hubs in regulatory networks, underscoring their diagnostic and pathogenic significance. In tolDCs from SLE donors, lipid metabolism pathways were selectively altered, suggesting impaired synthesis of pro-resolving lipid mediators. Additionally, diminished IL10RA expression and dysregulated IRF4 activity in SLE moDCs indicated intrinsic defects in IL-10 mediated tolerogenic differentiation.
CONCLUSION: Together, these findings suggest that interferon driven transcriptional rewiring, impaired IL-10 signaling, and aberrant lipid metabolic programming converge to compromise DCs tolerogenic capacity in SLE. This highlights key mechanistic pathways that could be targeted to restore immune tolerance and reduce chronic inflammation.