CD5L insufficiency exacerbates skeletal joint damage in rheumatoid arthritis

Abstract

CD5L is an immunoregulatory protein induced during inflammation and makes a life-saving contribution in infection and sepsis. Here, we explored the overall impact of CD5L in rheumatoid arthritis (RA). Using experimental RA models, we demonstrated an early surge of CD5L expression in wild-type mice, as well as a higher incidence and increased severity of arthritis in CD5L-deficient mice. In the blood, CD5L-deficient mice exhibited enhanced inflammation, a higher proportion of CD11b mononuclear cells, and elevated levels of IL-1{beta}, IL-17, and IFN-{psi}, particularly at the pre-clinical stage of arthritis. In human RA, mononuclear cells conditioned with CD5L, as well as endogenous CD5L production, were associated with reduced CD11b expression, increased IL-10 and PD-L1 production, and an enrichment of non-classical CD16+ monocytes. Analysis of the CD5L-dependent transcriptome in CD14 cells from RA patients revealed the acquisition of an efferocytosis profile, with upregulation of C1Q subunits, GAS6, AXL, and ALOX15B. It also showed signs of insufficient cargo processing, which dampens the resolution of inflammation, permits the expansion of IFN-primed non-classical monocytes, and correlates strongly with joint damage accrual. Despite markedly low CD5L levels in the synovium, RA synovial tissue was enriched with non-classical monocytes carrying the GAS6-AXL signature, which fosters osteoclast progenitors. In conclusion, this study demonstrates that the anti-inflammatory and inflammation-resolving properties of CD5L in experimental and human RA are mediated through the induction of efferocytosis-related and IFN-primed monocyte programs. This harbors a potential risk of uncontrolled invasion of non-classical monocytes into the synovial tissue, leading to joint structural damage. The complex role of CD5L in inflammation and disease outcomes requires careful consideration of the disease phase and experimental context.