DHA/AA alleviates LPS-induced Kupffer cells pyroptosis via GPR120 interaction with NLRP3 to inhibit inflammasome complexes assembly

Abstract

Pyroptosis is a novel type of programmed cell death associated with the pathogenesis of many inflammatory diseases. Docosahexaenoic acid (DHA) and Arachidonic acid (AA) is widely involved in inflammatory pathological processes. However, the effect and mechanism of DHA and AA on pyroptosis in Kupffer cells are poorly understood. The present study demonstrated that DHA and AA ameliorated lipopolysaccharide (LPS)-induced Kupffer cells pyroptosis by reversing the increased expression of NLRP3 inflammasome complex, GSDMD, IL-1β, IL-18, and PI-stained positive rate. Next, the study revealed that GPR120 silencing eliminated the anti-pyroptosis of DHA and AA in LPS-induced Kupffer cells, suggesting that DHA and AA exerted their effect through GPR120 signaling. Importantly, GPR120 endocytose and binds to NLRP3 under LPS stimulation. Furthermore, co-immunoprecipitation showed that DHA and AA promoted the interaction between GPR120 and NLRP3 in LPS-exposed Kupffer cells, thus inhibiting the self-assembly of NLRP3 inflammasome complex. Finally, the study verified that DHA and AA alleviated hepatic injury through inhibiting Kupffer cells pyroptosis in vivo. The findings indicated that DHA and AA alleviated LPS-induced Kupffer cells pyroptosis via GPR120 interaction with NLRP3, it might become a potential therapeutic approach hepatic injury.

GPR120 modulates epileptic seizure and neuroinflammation mediated by NLRP3 inflammasome

“…Hua et al also found that activation of NLRP3 and caspase-1 in neurons can also lead to neuroinflammation [40]. NLRP3 has been found to be significantly elevated in neurons [41] and microglia [42] in the epileptic brain, which is mainly stimulated by intracellular environment and cell membrane receptor signals [43]. Moreover, GPR120 is a membrane receptor that can be internalized into cells to regulate inflammatory factors under disease conditions [44].…”

“…Moreover, GPR120 is a membrane receptor that can be internalized into cells to regulate inflammatory factors under disease conditions [44]. When inflammation occurs, interaction of GPR120 and NLRP3 evokes internalization of GPR120 from the cell surface into internal cellular compartments, exerting anti-inflammatory effects [41]. However, such anti-inflammation of GPR120 is still not enough to compensate inflammatory damage in epilepsy; therefore, exogenous GPR120 is necessary for seizure alleviation.…”

Modulatory Properties of Food and Nutraceutical Components Targeting NLRP3 Inflammasome Activation

“…In particular, fish oil, a matrix particularly enriched in ω-3 DHA and EPA, has been extensively studied. All data reported the anti-inflammatory properties of EPA and DHA resulting in a downregulation of NLRP3 gene expression and in a decreased secretion of pro-inflammatory cytokines (IL-1β and IL-18) in obesity models [ 102 , 103 ], in DSS-induced colitis in mice [ 104 ], in LPS-induced Kupffer cells [ 105 ], and in both prefrontal cortex and hippocampus of rats [ 106 ]. Nevertheless, numerous studies have explored the anti-inflammatory mechanisms of PUFAs.…”

“…More recently, Quingyao et al assumed that DHA-mediated NLRP3 inflammasome inhibition was due to the blockade of high glucose-induced TXNIP via the PI3K/Akt pathway in pre-adipocytes [ 103 ]. Other mechanisms through which ω-3 PUFAs reduce metabolic inflammation may include the G protein-coupled receptor 120 (GPR120) and GPR40, which interact with NLRP3 and inhibited the NLRP3 inflammasome complex assembly [ 42 , 105 ].…”

Dietary fatty acids in gut health: Absorption, metabolism and function

“…( Liu et al., 2012 ) revealed that dietary fish oil enhanced the integrity of the intestines through inhibiting TLR4 and NOD2 signaling pathways within breastfed developing porcines post-LPS confrontation. Interestingly, n-3 PUFA, mainly EPA, are able to alleviate LPS-induced Kupffer cells pyroptosis via abolishing NLRP3 inflammasome activation, thus inhibiting subsequent release of cytokines ( Fan et al., 2021 ).…”