Mesenchymal Stromal Cells Immunosuppress Osteoarthritis Synovial Fluid Tolerized Monocytes via IL-6

The mechanism of mesenchymal stromal cell (MSC) interactions with monocytes/macrophages (MΦs) in knee osteoarthritis (KOA) is not fully understood. We report that synovial fluid (SF) MΦs are tolerized. Healthy donor-derived CD14 ⁺ peripheral monocytes partially mimic SF MΦs tolerization, but are also activated, immunosuppressed and functionally impaired after longer exposure to complex late-stage KOA SF matrix. Classical interleukin (IL)-6 signaling in late-OA SF immunosuppresses CD14 ⁺ monocytes via signal transducer and activator of transcription (STAT3) and suppressor of cytokine signaling (S OCS3 ), while toll-like receptor (TLR)4 via nuclear factor kappa-light-chain-enhancer of activated B (NF-κB) and c-Jun Terminal Kinase (JNK) drive CD14 ⁺ monocyte activation. Late-OA SF semi-tolerizes CD14 ⁺ monocytes with unchanged tumor necrosis factor (TNF) and CD86 expression with lipopolysaccharide (LPS) challenge. Addition of MSC(M) soluble factors enhances immunosuppression through IL-6 signaling, and nullifies late-OA SF activation effects by decreasing p-JNK and reducing TLR-mediated NF-κB and TNF. MSC(M) immunosuppressed CD14 ⁺ monocytes in late-OA SF are functionally rescued with improved phagocytosis.