Dietary Fatty Acid Regulation of the NLRP3 Inflammasome via the TLR4/NF‐κB Signaling Pathway Affects Chondrocyte Pyroptosis

Dietary fatty acid (FA) content and type have different effects on obesity‐associated osteoarthritis (OA), but the mechanisms underlying these differences are not fully understood. Inflammation activated by toll‐like receptor 4 (TLR4)/nuclear factor‐ (NF‐) κ B signaling and pyroptosis induced by the NLRP3/caspase‐1/gasdermin D (GSDMD) signaling pathway play important roles in OA development. Our aim in this study was to observe the effects of dietary FAs on the articular cartilage of obese post‐traumatic OA model mice and on chondrocytes stimulated by lipopolysaccharide (LPS) and to determine whether the underlying mechanisms involve TLR4/NF‐ κ B and NLRP3/caspase‐1/GSDMD signaling pathways. Mice were fed high‐fat diets rich in various FAs and underwent surgical destabilization of the medial meniscus to establish the obesity‐related post‐traumatic OA model. LPS‐induced SW1353 chondrosarcoma cells were used to mimic OA status in vitro , and TLR4 inhibitors or TLR4 overexpressing lentivirus was administered. Analysis using weight‐matched mice and multiple regression models revealed that OA was associated with dietary FA content and serum inflammatory factor levels, but not body weight. Diets rich in n‐3 polyunsaturated fatty acids (PUFAs) attenuated OA and inhibited the TLR4/NF‐ κ B and NLRP3/caspase‐1/GSDMD signaling pathways, whereas diets rich in saturated fatty acids (SFAs), monounsaturated fatty acids (MUFAs), or n‐6 PUFAs increased OA severity and activated these pathways. In vitro results for SFAs, n‐6 PUFAs, and n‐3 PUFAs were consistent with the animal experiments. However, those for MUFAs were not. FA effects on the NLRP3/caspase‐1/GSDMD pathway were associated with the inhibition or activation of the TLR4 signaling pathway. In conclusion, diets rich in SFAs or n‐6 PUFAs can exacerbate obesity‐associated OA, whereas those rich in n‐3 PUFAs have protective effects against this disease, due to their respective pro‐/anti‐inflammatory and pyroptotic effects. Further research on dietary FA supplements as a potential therapeutic approach for OA is needed.