Kynurenic acid inhibits macrophage pyroptosis by suppressing ROS production via activation of the NRF2 pathway

Abstract

Macrophage pyroptosis and related inflammatory responses play an important role in periodontitis. Kynurenic acid (KA) is hypothesized to have anti-inflammatory potential, but whether KA can inhibit macrophage pyroptosis and the underlying mechanisms remain unclear. Lipopolysaccharide (LPS) was used to induce pyroptosis in THP-1-derived macrophages. KA or ML385 was used to pretreat macrophages, after which, cell viability, NOD-like receptor protein 3 (NLRP3) inflammasome-related protein expression, oxidative stress levels and nuclear factor erythroid 2-related factor 2 (NRF2) expression were measured. The results showed that KA improved the LPS-induced decrease in macrophage viability and lactate dehydrogenase release. KA prevented THP-1 macrophage pyroptosis induced by LPS by reducing the expression of NLRP3, Gasdermin-D, and Caspase1, and decreased the expression of inflammatory factors. KA suppressed NLRP3 inflammasome activation by inhibiting ROS overproduction and increasing Heme Oxygenase 1 and glutathione levels. Moreover, KA promoted NRF2 translocation from the cytoplasm to the nucleus. In addition, the anti-pyroptotic and antioxidant effects of KA were reversed by ML385 inhibition of NRF2. In the present study, it was found that KA significantly suppressed macrophage pyroptosis induced by LPS. It was further demonstrated that the anti-pyroptotic effects of KA were mediated by activation of the NRF2 pathway.

MCL attenuates atherosclerosis by suppressing macrophage ferroptosis via targeting KEAP1/NRF2 interaction

“…Interestingly, unlike ox-LDL, ML385 increased cell ROS levels but did not affect macrophage viability. In the current manuscript, 5 μM ML385 was used to pretreat macrophages; according to previous literature [ 29 , 72 ], this concentration only inhibited NRF2 activity but did not damage the cells. Our data also explain the underlying mechanism by which we and previous literature have reported the antioxidant effects of MCL.…”

Anti-Inflammatory Effect of Chestnut Honey and Cabbage Mixtures Alleviates Gastric Mucosal Damage

“…CH, which is rich in polyphenols, has been useful in the treatment of inflammation-related chronic disorders because of its strong antioxidant action [16]. Additionally, previous studies have reported that CH contains a substantial amount of kynurenic acid (KA), a metabolite of tryptophan with potential anti-inflammatory properties [17][18][19][20]. Therefore, increasing the KA content in CH (KACH) may be a crucial factor for treating inflammation.…”

Copper Chelation Therapy Attenuates Periodontitis Inflammation through the Cuproptosis/Autophagy/Lysosome Axis

“…When pathogenic microbes invade periodontal tissues, a vast array of immune cells, such as macrophages, T cells, B cells, and dendritic cells, are recruited [ 14 ]. Macrophages play a crucial role in the destruction of periodontal tissues, where their heightened aggregation and activation lead to tissue lesion [ 15 , 16 , 17 , 18 ]. The buildup of inflammatory agents originating from macrophages in gingival tissues and crevicular fluid is linked to the intensity and advancement of periodontitis, while blocking their release is associated with improved bone resorption and the infiltration of inflammatory cells [ 19 , 20 ].…”

“…The buildup of inflammatory agents originating from macrophages in gingival tissues and crevicular fluid is linked to the intensity and advancement of periodontitis, while blocking their release is associated with improved bone resorption and the infiltration of inflammatory cells [ 19 , 20 ]. During the advancement of periodontal disease, recruited macrophages experience various forms of cell death, such as pyroptosis, necroptosis, and ferroptosis, leading to inflammatory cytokine sequences that intensify localized inflammation [ 16 , 21 , 22 , 23 ]. Significantly, macrophages act as key facilitators in pyroptosis, promoting the release of IL-1β, which, in turn, promotes periodontitis [ 22 ].…”