Monocytes and Neutrophils in Juvenile Idiopathic Arthritis

Abstract: Juvenile idiopathic arthritis (JIA) is a heterogenous inflammatory joint disease and the most commonrheumatic disease in children. Oligoarticular JIA (oJIA) is the major subgroup, which mainly affects fewand large joints, such as the knee. The immunological processes and key players driving inflammationwithin the affected joints are not well characterised. Research has primarily focused on adaptiveimmunity, and little is known of the contribution of the innate immune system. Neutrophils and monocytesare central members, with crucial roles as phagocytes, cytokine producers and regulators ofinflammation. Given the limited knowledge of the role of innate immunity in oJIA, we aimed tocharacterize the phenotype and function of monocytes and neutrophils in the arthritic joint.We found that synovial monocytes had both regulatory and pro-inflammatory features. For example, atthe surface level, they expressed markers of clearance and antigen presentation. This wascorrespondingly reflected at the mRNA level. Functionally, the synovial monocytes showed resistance tocytokine production upon further activation and had an increased efferocytosis. Additionally, they alsopromoted activation of healthy T-cells. Interestingly, we found that healthy monocytes acquired theregulatory features of synovial monocytes (both phenotypical- and fucntional features) through exposureto patient synovial fluid. This was primarily through the IL-6/JAK/STAT pathway. Furthermore, we showedthat the monocytes obtained the inflammatory features through cell-cell interactions, such as the abilityto promote T-cell activation. Specifically, we found that synovial fibroblasts induced this activation inhealthy monocytes in co-cultures in a contact-dependent manner, especially if the synovial fibroblastswere priorly exposed to synovial fluid. Indeed, this exposure to synovial fluid resulted in cytokineproduction and an enhanced ability to induce immune cell chemotaxis by the fibroblasts.Furthermore, we found that synovial neutrophils displayed signs of activation at the surface level, andthey had acquired a monocyte-like phenotype. This phenotype correlated with impaired effectorfunctions, primarily decreased phagocytosis ability and reactive oxygen species production. Interestingly,their phenotype could not be induced by stimulation of healthy neutrophils with synovial fluid, nor in cocultureswith synovial fibroblasts, suggesting that different mechanisms drive the neutrophil phenotype.Taken together, the results of this thesis describe the phenotype and role of synovial monocytes andneutrophils in the pathogenesis of oJIA, and emphasize potential underlying mechanisms driving theirphenotypes that could be utilized to develop therapies.