Abstract
BACKGROUND AND HYPOTHESIS: CD5L is a glycoprotein induced during inflammation and makes a life-saving contribution in infection and sepsis. Here, we explored the immunomodulatory effect of CD5L in rheumatoid arthritis (RA). We hypothesized that CD5L availability associates with systemic inflammatory activation during arthritis and stratifies monocyte programs linked to joint structural damage. METHODS: Using an experimental RA model, we assessed disease development and severity in wild-type and CD5L-deficient mice and characterized circulating immune cell populations and inflammatory mediators. In parallel, human RA mononuclear cells were conditioned with CD5L and analyzed phenotypically and transcriptionally, including CD5L-dependent transcriptome profiling of CD14⁺ cells and assessment of synovial tissue. Targeted pathway perturbations (HDAC inhibition, Lyn activation, Fcγ receptor engagement) were performed, followed by flow-cytometric phenotyping. These findings were integrated with clinical radiographic scoring and transcriptomic analyses in RA patient material. RESULTS: We observed an early surge of CD5L expression in wild-type mice and a higher incidence and increased severity of arthritis in CD5L-deficient mice. CD5L deficiency was associated with enhanced systemic inflammation, expansion of CD11b⁺ mononuclear cells, and elevated IL-1β, IL-17, and IFN-γ, particularly at the pre-clinical stage of arthritis. In human RA, CD5L-conditioned mononuclear cells, as well as endogenous CD5L production, were associated with reduced CD11b expression, increased IL-10 and PD-L1 production, and enrichment of non-classical CD16⁺ monocytes. CD5L-dependent transcriptomic profiling of CD14⁺ cells revealed an efferocytosis-like signature characterized by upregulation of C1Q subunits, GAS6, AXL, and ALOX15B. It also showed reduced expression of genes involved in cargo processing, coinciding with expansion of IFN-primed non-classical monocyte signatures. These CD5L-linked programs correlated strongly with joint damage accrual. Despite markedly low CD5L levels in the synovium, RA synovial tissue was enriched with GAS6-AXL⁺ non-classical monocyte signatures linked to osteoclast progenitor-associated signatures. CONCLUSION: This study identifies CD5L as an immunomodulatory factor in experimental and human RA and shows that CD5L availability is associated with efferocytosis-related and IFN-primed monocyte programs. Across experimental arthritis and RA patient material, these CD5L-linked programs correlate with non-classical monocyte expansion and structural joint damage, supporting a model in which CD5L marks a balance between inflammation resolution and monocyte trafficking linked to joint damage. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s10020-026-01456-x.