Synovial Monocytes Drive the Pathogenesis in Oligoarticular Juvenile Idiopathic Arthritis via IL-6/JAK/STAT Signalling and Cell-Cell Interactions

Abstract

AbstractObjectivesSynovial monocytes in oligoarticular juvenile idiopathic arthritis (oJIA) are polarized, but little is known of how they contribute to disease and attain their pathogenic features. The aim of this study was to investigate the role of monocytes in the pathogenesis of oJIA.MethodsThe function of synovial monocytes was analysed by several assays believed to reflect key pathogenic events, such as T-cell activation-, efferocytosis- and cytokine production assays through flow cytometry in untreated oJIA patients (n=33). The effect of synovial fluid on healthy monocytes was investigated through mass spectrometry, broad-spectrum phosphorylation assays and functional assays. Additional effects on monocytes were studied through co-cultures with primary fibroblast-like synoviocytes.ResultsThe results demonstrate that synovial monocytes display functional alterations, e.g., increased ability to induce T-cell activation, increased efferocytosis and resistance to cytokine production following activation with LPS.In vitro, synovial fluid induced regulatory features in healthy monocytes through an IL-6/JAK/STAT mechanism. The magnitude of synovial IL-6 driven activation in monocytes was reflected in circulating cytokine levels. An increased ability to induce T-cell activation and markers of antigen presentation could be induced by co-culture with fibroblast-like synoviocytes.ConclusionsSynovial monocytes in oJIA are functionally affected, drive chronic inflammation, and promote adaptive immune responses. This phenotype can be replicatedin vitrothrough a combination of synovial fluid (through IL-6/JAK/STAT) and cell-cell interactions. These data support a role of monocytes in the pathogenesis of oJIA and highlight a group of patients more likely to benefit from targeting the IL-6/JAK/STAT axis to restore synovial homeostasis.Key messagesWhat is already known on this topicMonocytes infiltrate the joint in oligoarticular juvenile idiopathic arthritis (JIA), where they display a pathogenic phenotype and signs of activationWhat this study addsThe results of this study demonstrate functional alterations of synovial monocytes in driving chronic inflammation in oligoarticular JIASynovial monocytes acquire their regulatory properties through the IL-6/JAK/STAT pathway in synovial fluid and their inflammatory properties through cell-cell interactionsIn patients with high IL-6/JAK/STAT involvement, this is reflected in elevated circulating cytokine levelsHow this study might affect research, practice or policyThis study describes the mechanisms controlling the function of synovial monocytes in oligoarticular JIA and identifies patients likely to respond to IL-6/JAK/STAT inhibition, which should be further explored to facilitate personalized medicine.