Dissection of the immune landscape in psoriatic arthritis defines immunoproteasome up-regulation in treatment resistance

作者：Reut Tzemach, Chamutal Gur, Truong San Phan, Eyal David, Mor Zada, Merav D. Shmueli, Kfir Mazuz, Fadi Sheban, Anna Kurilovich, Maya Ben Yehuda, Victoria Furer, Ari Polachek, Smadar Gertel, Nimrod Snir, Tali Eviatar, Sharon Nevo, Yifat Merbl, D. Paran, Shuang-Yin Wang, Ori Elkayam, Ido Amit · 发表于：Science Immunology · 年份：2025 · DOI：10.1126/sciimmunol.adu0284 · 被引用次数：6 · 研究领域：Autoimmune and Inflammatory Disorders Research、Spondyloarthritis Studies and Treatments、Psoriasis: Treatment and Pathogenesis

Despite substantial advancements in psoriatic arthritis (PsA) treatment modalities, a considerable proportion of patients continue to experience persistent joint inflammation, unresponsive to the armamentarium of disease-modifying antirheumatic drugs. Identifying previously unknown biomarkers and targets for refractory disease is urgently needed. Here, using single-cell RNA sequencing of synovial fluid from 41 patients with PsA and 9 osteoarthritis (OA) controls, we mapped the immune landscape of the pathogenic synovial fluid in patients with PsA. Our analysis revealed profound alterations in the myeloid compartment, primarily in type 2 conventional dendritic cells and monocytes. A comparison of these myeloid programs in PsA patient groups identified elevated expression of genes associated with the immunoproteasome and major histocompatibility complex class I as a major perturbation in refractory patients. Functional in vivo and in vitro experiments using a selective immunoproteasome inhibitor attenuated the activated myeloid compartment and disease manifestations. Our research imparts critical insights into PsA pathogenesis, potentially paving a way for targeted therapeutic interventions in treatment-resistant patients.