Dissection of the immune landscape in psoriatic arthritis defines immunoproteasome up-regulation in treatment resistance
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.
Authors
- Victoria Furer (ORCID: https://orcid.org/0000-0001-5193-4207)
- Chamutal Gur (ORCID: https://orcid.org/0000-0001-5191-2956)
- D. Paran
- Nimrod Snir (ORCID: https://orcid.org/0000-0002-7417-3567)
- Anna Kurilovich (ORCID: https://orcid.org/0000-0002-3952-8609)
- Reut Tzemach
- Eyal David (ORCID: https://orcid.org/0000-0002-9020-2364)
- Ari Polachek (ORCID: https://orcid.org/0000-0002-2411-8084)
- Yifat Merbl (ORCID: https://orcid.org/0000-0002-3465-2221)
- Fadi Sheban (ORCID: https://orcid.org/0009-0008-2819-6953)
- Smadar Gertel (ORCID: https://orcid.org/0000-0001-7949-7184)
- Ido Amit (ORCID: https://orcid.org/0000-0003-2968-877X)
- Truong San Phan (ORCID: https://orcid.org/0000-0002-8837-5119)
- Merav D. Shmueli (ORCID: https://orcid.org/0000-0002-9196-7633)
- Ori Elkayam (ORCID: https://orcid.org/0000-0001-9329-3639)
- Mor Zada (ORCID: https://orcid.org/0000-0002-9204-8460)
- Sharon Nevo
- Tali Eviatar (ORCID: https://orcid.org/0000-0002-2894-4033)
- Kfir Mazuz (ORCID: https://orcid.org/0009-0006-7113-0525)
- Shuang-Yin Wang (ORCID: https://orcid.org/0000-0001-9683-4103)
- Maya Ben Yehuda (ORCID: https://orcid.org/0009-0000-8059-2656)
Institutions
- Tel Aviv University (IL)
- Hebrew University of Jerusalem (IL)
- Tel Aviv Sourasky Medical Center (IL)
- Hadassah Medical Center (IL)
- Weizmann Institute of Science (IL)
Publication Details
- Journal
- Science Immunology
- Published
- 2025-06-06
- DOI
- https://doi.org/10.1126/sciimmunol.adu0284
- Citations
- 4
- Primary Topic
- Autoimmune and Inflammatory Disorders Research
- Type
- article
- Field-Weighted Citation Impact
- 7.08