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

Abstract

Objective: 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.

Methods: 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.

Results: 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.

Conclusion: 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.