Single‐Cell Transcriptomics Reveals Macrophage‐Enriched Serine Dehydratase Associated With Sterile Joint Inflammation: Implications for Rheumatic Immune‐Related Adverse Events
Ling Zhou, Shaohua Ju, Kun Wang, Liuwei Gu, Siqi Song, Yuchen Zhu, Ruicheng Wu, Benxiang He, Yushi HuBackground
As immune checkpoint inhibitors (ICIs) reshape cancer therapy, clinicians increasingly encounter complex inflammatory complications, notably rheumatic immune‐related adverse events (irAEs). Sterile joint inflammation, often overlapping with pre‐existing osteoarthritis (OA), presents a major diagnostic and management challenge in immunocompromised patients. Dysregulated serine metabolism has emerged as a potential contributor to macrophage activation in such sterile inflammatory states, yet its precise role remains poorly defined. This study investigates serine metabolism‐related cellular heterogeneity to provide actionable insights into macrophage‐driven joint inflammation.
Methods
Bulk transcriptomic datasets from multiple GEO cohorts were integrated with machine learning algorithms to identify serine metabolism‐related genes in OA. Single‐cell RNA‐sequencing data were analyzed with Seurat, and intercellular communication was inferred using CellChat. In vitro, interleukin‐1β (IL‐1β)/tumor necrosis factor‐α (TNF‐α)/lipopolysaccharide (LPS)‐stimulated chondrocytes were transfected with siRNAs targeting serine dehydratase (SDS), and functional outcomes were assessed by CCK‐8, flow cytometry, qRT‐PCR, western blot, and enzyme‐linked immunosorbent assay. A Transwell co‐culture system with M1 macrophages was established to evaluate macrophage–chondrocyte crosstalk.
Results
SDS was upregulated in OA and showed moderate discriminatory ability for distinguishing OA from controls. scRNA‐seq revealed predominant macrophage enrichment of SDS, immune deconvolution linked SDS expression to macrophage infiltration, and SDS‐positive macrophages showed altered outgoing interactions with fibroblasts and endothelial cells, alongside activation of TNF‐α, nuclear factor κ‐B (NF‐κB), and cytokine–cytokine receptor signaling SDS knockdown in chondrocytes reduced matrix metallopeptidase 13 (MMP13), restored collagen type II alpha 1 chain (COL2A1), and decreased TNF‐α secretion, while suppressing proliferation and promoting apoptosis. These effects were partially reversed by M1 macrophage co‐culture, indicating that macrophage‐derived signals modulate the chondrocyte response to SDS deficiency.
Conclusion
SDS acts as a macrophage‐enriched metabolic regulator linking serine metabolism to sterile joint inflammation and cartilage degradation. Targeting this metabolic‐immune axis offers a potential strategy for the clinical management of treatment‐associated rheumatic toxicities in oncology, potentially allowing for the control of localized inflammation without requiring broad immunosuppression that might compromise systemic antitumor efficacy.