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

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.