Free fatty acids: potential proinflammatory mediators in rheumatic diseases

Abstract

Objectives Due to their role in inflammatory metabolic diseases, we hypothesised that free fatty acids (FFA) are also involved in inflammatory joint diseases. To test this hypothesis, we analysed the effect of FFA on synovial fibroblasts (SF), human chondrocytes and endothelial cells. We also investigated whether the toll-like receptor 4 (TLR4), which can contribute to driving arthritis, is involved in FFA signalling. Methods Rheumatoid arthritis SF, osteoarthritis SF, psoriatic arthritis SF, human chondrocytes and endothelial cells were stimulated in vitro with different FFA. Immunoassays were used to quantify FFA-induced protein secretion. TLR4 signalling was inhibited extracellularly and intracellularly. Fatty acid translocase (CD36), responsible for transporting long-chain FFA into the cell, was also inhibited. Results In rheumatoid arthritis synovial fibroblasts (RASF), FFA dose-dependently enhanced the secretion of the proinflammatory cytokine IL-6, the chemokines IL-8 and MCP-1, as well as the matrix-degrading enzymes pro-MMP1 and MMP3. The intensity of the response was mainly dependent on the patient rather than on the type of disease. Both saturated and unsaturated FFA showed similar effects on RASF, while responses to the different FFA varied for human chondrocytes and endothelial cells. Extracellular and intracellular TLR4 inhibition as well as fatty acid transport inhibition blocked the palmitic acid-induced IL-6 secretion of RASF. Conclusions The data show that FFA are not only metabolic substrates but may also directly contribute to articular inflammation and degradation in inflammatory joint diseases. Moreover, the data suggest that, in RASF, FFA exert their effects via TLR4 and require extracellular and intracellular access to the TLR4 receptor complex.

Differential impact of obesity on the pathogenesis of RA or preclinical models is contingent on the disease status

“…Consistently, earlier studies show that while fatty acids like palmitate degrade IκB in WT mouse peritoneal macrophages, nuclear factor-κB signalling is impaired in TLR4−/− cells 44. Notably, activation of TLR4 by free fatty acids is not restricted to macrophages since a recent paper demonstrates that RA ST fibroblasts stimulated by unsaturated and saturated fatty acids produce pro-inflammatory factors via TLR4 signalling 52. However, it is unclear whether fatty acids can directly bind to TLR4 or if they participate in receptor dimerisation procedure 53 54.…”

Effects of Dietary Saturated Fatty Acids on the Onset and Progression of Osteoarthritis in Rat Knee Joints

“…Circulation of FFA usually is known to be one of the causative agents of diseases associated with increased lipid content in the body, such as obesity [172,173]. The increased levels of intercellular FFA usually occur due to the imbalance of FFA synthesis and utilization.…”

“…The SFA-BSA complex solutions were made using a protocol described earlier [173]. Individual SFA was sterile-filtered (0.45μM filter) prior to application to the cell cultures using a protocol described earlier [173]. The vehicle control (negative control) was the fatty acid free-BSA with the same concentration of ethanol.…”

“…Bovine serum albumin (BSA) (fatty acid free, Sigma-Aldrich) was chosen as the carrier. The SFA-BSA complex solutions were made using a protocol described earlier [173]. Individual SFA was sterile-filtered (0.45μM filter) prior to application to the cell cultures using a protocol described earlier [173].…”

“…Increased intake of either mono-or poly-unsaturated fatty acids in a healthy population of middle-aged adults was linked with increased possibility of developing bone marrow lesions [145]. Also, free fatty acids may be involved in inflammatory metabolic diseases such as obesity and inflammatory joint diseases [173]. Thus, dietary saturated fatty acids (SFA) could initiate the link between OA and obesity [121,223,224].…”