Monocyte and macrophage polarization in systemic juvenile idiopathic arthritis and macrophage activation syndrome
Systemic juvenile idiopathic arthritis is a severe inflammatory disease of childhood conferring significant risk for fatal complications including Macrophage Activation Syndrome (MAS). The phenotype and function of the key effector monocytes and macrophages in systemic JIA remains unclear. These cells adopt distinct polarization states based on specific activating signals, modified by microRNA to “fine-tune” these transcriptional responses. Circulating monocytes in systemic JIA appear to display a unique mixed polarization phenotype, and little is known regarding how tissue resident macrophages are further altered during emergence of MAS (Image 1). Notably, despite effective treatment children with systemic JIA remain at risk for MAS. Thus, there is a critical need to characterize the phenotype of monocytes and tissue macrophages in systemic JIA, and particularly how they contribute to emergence of MAS. In the absence of such knowledge, developing novel strategies to effectively prevent and treat MAS will remain a formidable challenge.
The objective in this project is to define polarization-specific gene expression signatures and functional roles of microRNA in monocytes and macrophages from children with systemic JIA and a mouse model of systemic JIA/MAS. Our central hypothesis is monocytes from children with systemic JIA have a distinct polarized pattern which is regulated by microRNA, and further dysregulated during MAS. This project will utilize emerging technologies to define the molecular control of polarization-specific transcriptional signatures in monocytes and macrophages in children with systemic JIA and MAS. Together these findings are expected to have positive translational impact, through providing new targets to modulate inflammation in systemic JIA and reduce the risk for MAS.
Funding: NIAMS/NIH, K08-AR072075