Resident synovial macrophages in synovial fluid: Implications for immunoregulation.

Resident synovial macrophages (RSMs) are anti-inflammatory, self-renewing macrophages that provide physical immune sequestration of the joint space from the peripheral immune system. Increased permeability of this structure is associated with peripheral immune cells in the synovial fluid (SF). Direct measures of synovial barrier integrity are possible with tissue histology, but after barrier breakdown, if these cells perpetuate or initiate chronic inflammation in SF remains unknown. We sought to identify RSM in human SF as an indirect measure of synovial barrier integrity. To validate findings, we created a novel ex vivo explant model using human synovium. scRNA-seq revealed these SF RSMs upregulated pro-fibrotic and pro-osteoclastic pathways in inflammatory arthritis, but not septic arthritis. Increased frequencies of RSMs in SF was associated with increased sRANKL regardless of underlying pathology. These findings suggest the frequency of RSMs in SF may correlate with synovial barrier damage and in turn, potential damage to joint structures.