New research revealed that Notch signaling pathways may play a crucial role in early active rheumatoid arthritis but are not significantly involved in established disease.
In the study, published in Arthritis & Rheumatology, researchers demonstrated that Notch ligands and receptors were enriched during early active rheumatoid arthritis (RA), particularly during neovascularization.
Further, JAG1/2, DLL1/4, and Notch1/3 were expressed at higher levels in early, rather than established, disease. Power Doppler ultrasound imaging confirmed that JAG1/2, DLL1, and Notch3 were involved in joint neovascularization during early active RA.
Tumor necrosis factor (TNF) played a central role in Notch ligand expression, with anti-TNF responders showing JAG1/2 and DLL1/4 transcriptional downregulation in RA synovial tissue myeloid cells. In anti-TNF good responders (defined as ΔDAS28 > 1.2 with DAS28 ≤ 3.2 at 12 weeks), this downregulation occurred in myeloid cells but not in fibrotic pathotypes.
The research revealed distinct cellular expression patterns. DLL4 showed high expression across macrophages, fibroblast-like synoviocytes (FLS), and endothelial cells, whereas other Notch ligands were predominantly expressed on RA macrophages and FLS. Notch receptors demonstrated high expression on RA macrophages with intermediate levels on FLS and endothelial cells.
Treatment response varied significantly. Anti-interleukin (IL)-6R antibody therapy only affected DLL4 expression. Triple disease-modifying antirheumatic drug (DMARD) therapy (hydroxychloroquine + sulfasalazine + methotrexate) reduced JAG1, Notch3, and HEY1 transcription. Tofacitinib showed no effect on Notch family members in macrophage and FLS cocultures, highlighting limited involvement of JAK/STAT signaling in Notch regulation.
The pathway appeared less critical during the erosive stage, as there was no statistically significant difference in Notch ligand/receptor expression between patients with or without radiographic erosion. Synovial thickness evaluated by ultrasound showed no correlation with JAG1/2, DLL1/4, and Notch1/3 transcription levels.
Molecular analysis revealed that TNF-alpha increased Notch3 expression in macrophages, further amplified by RA FLS addition. Toll-like receptors and TNF were common inducers of Notch expression in RA macrophages, FLS, and endothelial cells. The research showed that NF-κB, MAPK, and AKT pathways were involved in Notch signaling, while JAK/STATs were not.
Conflict of interest disclosures were not made available at the time of publishing.