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

Abstract

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-) κB 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-κB 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-κB 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.

The sirtuin family in health and disease

“…90,91 It is believed that activation of the NLRP3 inflammasome occurs in two sequential steps -first, it must be primed, and then it can be activated. 71 When the body suffers from inflammatory disease, damage-associated molecules directly engage TLR4 and then quickly activate the NF-κB signaling pathway, resulting in augmented expression of NLRP3; [92][93][94] this in turn generates inflammatory cytokines such as IL-1β, IL-18, TNF-α and transforming growth factor-beta (TGF-β) which aggravate inflammation. 95 Some studies have found that SIRTs, especially SIRT1 and SIRT3, act on NLRP3 to exert anti-inflammatory functions.…”

Recent Therapeutic Strategies for Excessive Chondrocyte Death in Osteoarthritis: A Review

“…Both loganin and morroniside have been confirmed to reduce chondrocyte pyroptosis and inflammation response through inhibiting activation of NF‐κB 84,85 . Study found that a diet rich in unsaturated fatty acids can play an anti‐inflammatory and anti‐pyroptotic effect to alleviate OA by inhibiting TLR4/NF‐κB axis and NLRP3/caspase‐1/GSDMD axis 171 . Moreover, hypoglycemic agent metformin reduced chondrocyte pyroptosis in an OA rat model by inhibiting NLRP3 172 .…”

“…84,85 Study found that a diet rich in unsaturated fatty acids can play an anti-inflammatory and anti-pyroptotic effect to alleviate OA by inhibiting TLR4/NF-κB axis and NLRP3/caspase-1/GSDMD axis. 171 Moreover, hypoglycemic agent metformin reduced chondrocyte pyroptosis in an OA rat model by inhibiting NLRP3. 172 Mesenchymal stem cell-derived exosomes, micro-RNAs, phytochemical, growth factors, biological enzymes, and exercise all exhibit good potential to inhibit chondrocyte pyroptosis.…”

IRAK4 in the hippocampus increases susceptibility to seizures through NF-κB/NLRP3-mediated neuronal pyroptosis

“…This indicates that IRAK4 can act through the activation of NF-κB. NF-κB can promote the transcription of NLRP3, leading to the occurrence of pyroptosis [17]. NF-κB is involved in the pathophysiology of various central nervous system diseases, including epilepsy [18] and brain hemorrhage [19].…”