PD‐L1‐expressing macrophages play a protective role in the joint during arthritis

Abstract

ObjectivesArthritis associated with immune checkpoint inhibitor (ICI) therapies highlights the importance of immune checkpoint expression for joint homeostasis. We investigated the role of programmed death ligand 1 (PD‐L1) in the synovium using collagen‐induced arthritis (CIA) mouse model.MethodsWe blocked PD‐L1 using blocking antibodies (Abs) during CIA and assessed the arthritis severity by clinical and histological scoring. PD‐L1 expression and origin of synovial macrophages were investigated using flow cytometry and parabiosis. We utilized 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 RT‐PCR, flow cytometry, and single‐cell RNA sequencing.ResultsAnti‐PD‐L1 Ab 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 MerTK and IL‐10 expression during acute CIA. Genetic depletion of PD‐L1 on macrophages in LyzcrePD‐L1fl/fl mice resulted in worsened CIA compared with controls. We found that human PD‐L1+ macrophages in the healthy and rheumatoid arthritis synovium express MerTK and IL‐10.ConclusionsPD‐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.This article is protected by copyright. All rights reserved.