Abstract
Fibroblast-like synoviocytes (FLSs) are a major cell population of the pannus that invades cartilage and bone in rheumatoid arthritis (RA). FLS resistance to apoptosis is a major characteristic of RA. The aims of this study were to investigate the effects of interleukin-17 (IL-17) and IL-17-producing T helper (Th17) cells on resistance to apoptosis in FLSs from RA patients (RA FLSs) and their roles in mitochondrial dysfunction and autophagy. Mitochondrial function was assessed in RA FLSs and FLSs from osteoarthritis patients (OA FLSs). FLSs were treated with IL-17 and their morphological features, respiratory level and mitochondrial gene expression were measured. The effects of IL-17 and Th17 cells on the relationship between autophagy and apoptosis were evaluated by measuring the expression of apoptosis-related genes using sodium nitroprusside or 3-methyladenine. The mitochondria of FLSs isolated from RA and osteoarthritis patients displayed different morphological and physiological features. RA FLSs exhibited greater autophagosome formation and greater dysfunction of mitochondrial respiration compared with OA FLSs. IL-17 induced mitochondrial dysfunction and autophagosome formation in RA FLSs, suggesting that they were resistant to apoptosis. Autophagy-related antiapoptosis induced by IL-17 was restored by inhibition of autophagy, suggesting a relationship between mitochondrial dysfunction and cell survival in RA FLSs. Th17 cells and IL-17 increased autophagy of RA FLSs by causing mitochondrial dysfunction. Our findings suggest that, in RA, interactions between RA FLSs and Th17 cells may be involved in the tumorous growth of FLSs and the formation of pannus in joints.
Highlights
Rheumatoid arthritis (RA) is the most common autoimmune disease and is characterized by progressive joint destruction and functional disability in affected people
To investigate the mitochondrial dysfunction of RA Fibroblast-like synoviocytes (FLSs), the morphologic changes of mitochondria were investigated in RA and OA FLSs isolated from synovia
We investigated the possible mechanisms responsible for the effects of Th17 cells and interleukin 17 (IL-17) on mitochondrial dysfunction in RA FLSs
Summary
Rheumatoid arthritis (RA) is the most common autoimmune disease and is characterized by progressive joint destruction and functional disability in affected people. Accumulating scientific evidence shows that interleukin 17 (IL-17) and IL-17-producing T helper (Th17) cells play critical roles during the development and progression of RA.[2,3] the exact pathogenesis of RA remains unclear, data from experimental models suggest that IL-17 plays a role in pannus growth,[4] structural destruction of rheumatoid joints through receptor activator of nuclear factor κB ligand-independent osteoclastogenesis,[5] and synovial neoangiogenesis.[6]. Autophagy plays a crucial role in immunity and inflammation.[23] Excessive production of reactive oxygen species (ROS) by defective mitochondria may initiate inflammation.[24] Mitochondrial oxidative stress caused by infection or inflammatory disease increases the secretion of chemokines and inflammatory cytokines, which stimulate infiltration by lymphocytes such as T helper (Th) cells.[25] Mutations in mitochondrial genes are related to the pathogenesis and local inflammation involved in RA.[26,27]
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