Programmed Death Ligand 1-Expressing Macrophages and Their Protective Role in the Joint During Arthritis.

Abstract

Arthritis associated with immune checkpoint inhibitor therapies highlights the importance of immune checkpoint expression for joint homeostasis. We investigated the role of programmed death ligand (PD-L) 1 in the synovium using a collagen-induced arthritis (CIA) mouse model. We blocked PD-L1 using blocking antibodies during CIA and assessed the arthritis severity by clinical and histologic scoring. PD-L1 expression and the origin of synovial macrophages were investigated using flow cytometry and parabiosis. We used Cre-Lox mice to ascertain the protective role of PD-L1-expressing macrophages in arthritis. The immune profile of human and murine synovial PD-L1⁺ macrophages was determined by reverse transcriptase-polymerase chain reaction, flow cytometry, and single-cell RNA sequencing. Anti-PD-L1 antibody treatment during CIA worsened arthritis with increased immune cell infiltration compared with isotype control, supporting the regulatory role of PD-L1 in the joint. The main cells expressing PD-L1 in the synovium were macrophages. Using parabiosis, we showed that synovial PD-L1⁺ macrophages were both locally proliferating and partially replaced by the circulation. PD-L1⁺ macrophages had increased levels of MER proto-oncogene tyrosine kinase (MerTK) and interleukin (IL)-10 expression during acute CIA. Genetic depletion of PD-L1 on macrophages in Lyz^crePD-L1^fl/fl mice resulted in worsened CIA compared with controls. We found that human PD-L1⁺ macrophages in the synovium of healthy individuals and patients with rheumatoid arthritis express MerTK and IL-10. PD-L1⁺ macrophages with efferocytotic and anti-inflammatory characteristics protect the synovium from severe arthritis in the CIA mouse model. Tissue-protective, PD-L1-expressing macrophages are also present in the human synovium at homeostasis and during rheumatoid arthritis.