Deciphering cell-cell interaction between Fibroblasts and Monocytes in oligoarticular Juvenile Idiopathic Arthritis

Abstract

Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in children and is characterized by chronic synovial inflammation. Monocytes isolated from inflamed joints in oligoarticular JIA display both inflammatory and regulatory features. While some insights exist regarding signals that drive regulatory traits, the mechanisms responsible for inflammatory activation remain poorly understood. Prior studies suggest that direct contact with synovial fibroblasts may play a central role in this process. Here, a co-culture model was used to explore how fibroblasts contribute to monocyte activation. Primary synovial fibroblasts from healthy donors and JIA patients were co-cultured with monocytes from healthy donors. Monocyte activation was assessed by surface marker expression (CD86, HLA-DR, CD16 and MerTK) and IL-6 secretion. To investigate potentially relevant mechanisms of contact-dependent activation, blocking strategies targeting αV-integrins on fibroblasts and CD18 on monocytes were applied. Co-culture consistently induced inflammatory monocyte activation (upregulation of CD86, HLA-DR and IL-6), independent of fibroblast donor origin. Blocking strategies had no clear inhibitory effect, suggesting that activation is not dependent on the integrin pathways -tested. Moreover, development of a CRISPR/Cas9 method failed in synovial fibroblasts but succeeded using dermal fibroblasts. Importantly, dermal fibroblasts induced comparable monocyte activation to that of synovial fibroblasts, demonstrating their relevance for functional studies. Taken together, our data show that synovial fibroblasts induce contact-dependent monocyte activation through mechanisms that remain to be defined, and support the use of dermal fibroblasts as a model for future research.

Popular Abstract

Investigating fibroblast-monocyte interactions as drivers of inflammation in Juvenile Idiopathic Arthritis

Can a seemingly harmless cell interaction alone be enough to trigger inflammation? We investigated whether the interaction between local joint cells and immune cells could spark the immune response seen in Juvenile idiopathic arthritis, a painful disease affecting children.

Juvenile idiopathic arthritis (JIA) is the most common type of arthritis in children. It’s a chronic autoimmune condition where the immune system mistakenly targets the joints, causing inflammation that leads to pain, stiffness and swelling. Although treatments can manage symptoms, there is still no cure. Many children continue to live with active disease well into their teenage years or even adulthood, which highlights the need for more targeted therapies. It’s still a mystery why the immune system starts attacking the joints in JIA. In this study, we set out to investigate whether a simple interaction between two common cell types might help explain what sets off the inflammation. We focused on fibroblasts collected from the joints of both healthy donors and children with JIA. These cells normally help maintain the structure and function of the joint. The second cell type in focus were monocytes, which are white blood cells that are part of the immune system’s first wave of action. Monocytes are known to become activated in the joints of children with JIA, but what causes this activation is still unclear. Recent research suggests that fibroblasts might be involved, possibly “encouraging” monocytes to become active, although exactly how this happens remains unknown. By studying the interaction between these two cell types more closely, this study aimed to improve our understanding of the immune imbalance in JIA and contribute to the development of better treatment strategies.

With this goal in mind, we studied what happened when the two cell types were brought into direct contact. The effect was strong and consistent. Monocytes showed clear signs of inflammatory activation after contact with fibroblasts, surprisingly even when the fibroblasts came from healthy joints. This response happened without any external trigger, suggesting that contact between fibroblasts and monocytes alone is enough to start the reaction. We also tried to block certain molecules found on the surface of fibroblasts and monocytes, that may enable communication between them. But even when these were blocked, the monocytes still became activated, which could mean that the cells rely on other molecules, or use more than one way to communicate with each other. To investigate further, we wanted to remove the contact molecules completely, rather than just block them. Because fibroblasts from joints are difficult to modify, we used another type of fibroblast that could activate monocytes in a similar way but was easier to work with. By editing their genes, we removed one of the surface molecules, creating a model for more detailed studies of how the cell contact might lead to immune activation.

Although much remains to be discovered, our findings point to a role for fibroblast and monocyte interactions in JIA and may help guide research toward uncovering what specifically drives the inflammation and bring us closer to better treatments for the affected children.

• author: Ivarsson, Vendela
• supervisor: Tobias Schmidt; Anki Mossberg
• organization: Department of Immunotechnology
• course: KIMM05 20251
• year: 2025
• type: H2 - Master's Degree (Two Years)
• subject: Technology and Engineering
• language: English
• id: 9201640
• date added to LUP: 2025-06-18 10:36:29
• date last changed: 2025-06-18 10:36:29