Synovial innate immune exhaustion is associated with worse pain in knee osteoarthritis

Objective Uncontrolled pain remains a major clinical challenge in the management of knee osteoarthritis (OA), the most common disabling joint disease. Worse pain is associated with synovial innate immune cell infiltration (synovitis), but the role of innate immune regulatory cells in pain is unknown. Our objective was to identify synovial innate immune cell subsets and pathophysiologic mechanisms associated with worse pain in patients with knee OA. Methods Synovial tissue biopsies from 122 patients with mild to severe knee OA pain (Knee injury and OA Outcome Score; KOOS) were analyzed to identify associations between synovial histopathology and worse pain. We then used spatial transcriptomics and proteomics of synovial tissue microenvironments (n=32), followed by single cell RNA sequencing (n=8), to identify synovial cell composition and cell‐cell communication networks in patients with more severe OA pain. Results Histopathological signs of synovial microvascular dysfunction, perivascular edema, were associated with worse KOOS pain (‐10.76 [95%CI ‐18.90, ‐2.61]). Patients with worse pain had fewer immune‐regulatory macrophages, expanded fibroblast subsets, and enrichment in neurovascular remodeling pathways. Synovial macrophages from patients with worse pain expressed markers of immune exhaustion, decreased phagocytic function (‐19.42% [95%CI ‐35.96, ‐2.89]) and their conditioned media increased neuronal cell stress in dorsal root ganglia. Conclusions Although synovitis increases during OA, our findings suggest that exhaustion, dysfunction, and loss of immune‐regulatory macrophages is associated with worse pain and may be an important therapeutic target.