Critical Role of Synovial Tissue–Resident Macrophage and Fibroblast Subsets in the Persistence of Joint Inflammation

Abstract

Rheumatoid arthritis (RA) is a chronic prototypic immune-mediated inflammatory disease which is characterized by persistent synovial inflammation, leading to progressive joint destruction. Whilst the introduction of targeted biological drugs has led to a step change in the management of RA, 30-40% of patients do not respond adequately to these treatments, regardless of the mechanism of action of the drug used (ceiling of therapeutic response). In addition, many patients who acheive clinical remission, quickly relapse following the withdrawal of treatment. These observations suggest the existence of additional pathways of disease persistence that remain to be identified and targeted therapeutically. A major barrier for the identification of therapeutic targets and successful clinical translation is the limited understanding of the cellular mechanisms that operate within the synovial microenvironment to sustain joint inflammation. Recent insights into the heterogeneity of tissue resident synovial cells, including macropahges and fibroblasts has revealed distinct subsets of these cells that differentially regulate specific aspects of inflammatory joint pathology, paving the way for targeted interventions to specifically modulate the behaviour of these cells. In this review, we will discuss the phenotypic and functional heterogeneity of tissue resident synovial cells and how this cellular diversity contributes to joint inflammation. We discuss how critical interactions between tissue resident cell types regulate the disease state by establishing critical cellular checkpoints within the synovium designed to suppress inflammation and restore joint homeostasis. We propose that failure of these cellular checkpoints leads to the emergence of imprinted pathogenic fibroblast cell states that drive the persistence of joint inflammation. Finally, we discuss therapeutic strategies that could be employed to specifically target pathogenic subsets of fibroblasts in RA.

Aromatase Inhibitor Induced Musculoskeletal Inflammation is Observed Independent of Oophorectomy in a Novel Mouse Model

“…Consequently, these results suggest that the pathogenesis of letrozole-induced genetic responses may be derived from cell types other than PBMCs. In concordance, the interaction of synovial fibroblasts with tissue resident macrophages has been shown to be associated with synovitis in autoimmune disease pathogenesis [29]. In this model of rheumatoid arthritis, fibroblast secretion of IL-6, CXCL12, and CCL2 in the synovial microenvironment as well as expression of an IFN-γ gene signature stimulates the macrophage-mediated inflammatory response.…”

Diagnostic Value of Neutrophil-to-Lymphocyte, Platelet-to-Lymphocyte, and Monocyte-to-Lymphocyte Ratios for the Assessment of Rheumatoid Arthritis in Patients with Undifferentiated Inflammatory Arthritis

“…Neutrophils, platelets, monocytes/macrophages, and lymphocytes are known to be actively involved in the pathogenesis of RA [ 30 , 31 , 32 , 33 , 34 , 35 ]. Monocytes circulate in the bloodstream and migrate into the inflamed synovium, where they can differentiate into macrophages.…”

The synovial fluid fibroblast-like synoviocyte: A long-neglected piece in the puzzle of rheumatoid arthritis pathogenesis

“…The term synovium refers to a thin membrane that encapsulates the joint cavity (39). This membrane is divided into two regions: the intima or synovial lining composed of intimal lining FLS and macrophages, and the sub-lining layer or sub-intima that contains principally sub-lining FLS, macrophages and adipose cells (40,41). During RA, FLS hyperplasia occurs in both locations (42).…”