The NRF2‑PGC‑1β pathway activates kynurenine aminotransferase 4 via attenuation of an E3 ubiquitin ligase, synoviolin, in a cecal ligation/perforation‑induced septic mouse model

Abstract

Sepsis‑associated encephalopathy (SAE) is a systemic inflammatory response syndrome of which the precise associated mechanisms remain unclear. Synoviolin (Syvn1) is an E3 ubiquitin ligase involved in conditions associated with chronic inflammation, including rheumatoid arthritis, obesity, fibrosis and liver cirrhosis. However, the role of Syvn1 in acute inflammation is not clear. The aim of the present study was to investigate the role of Syvn1 in a septic mouse model induced by cecal ligation/perforation (CLP). Metabolome analysis revealed that kynurenine (KYN), a key factor for the development of neuroinflammation, was increased in CLP‑induced septic mice. Notably, KYN was not detected in CLP‑induced septic Syvn1‑deficient mice. KYN is converted to kynurenic acid (KYNA) by kynurenine aminotransferases (KATs), which has a neuroprotective effect. The expression of KAT4 was significantly increased in Syvn1‑deficient mice compared to that in wild‑type mice. Promoter analysis demonstrated that Syvn1 knockdown induced the KAT4 promoter activity, as assessed by luciferase reporter activity, whereas Syvn1 overexpression repressed this activity in a dose‑dependent manner. Furthermore, the KAT4 promoter was significantly activated by the transcriptional factors, NF‑E2‑related factor 2 and peroxisome proliferator‑activated receptor coactivator 1β, which are targets of Syvn1‑induced degradation. In conclusion, the results of the current study demonstrates that the repression of Syvn1 expression induces the conversion of neurotoxic KYN to neuroprotective KYNA in a CLP‑induced mouse model of sepsis, and that Syvn1 is a potential novel target for the treatment of SAE.

Alterations in rat prefrontal cortex kynurenic acid levels are involved in the enduring cognitive dysfunctions induced by tetrahydrocannabinol exposure during the adolescence

“…This hypothesis is supported by the increase in KYNA levels induced by the addition of interleukin 6 to cultured human astrocytes, and the increased astrocytic activity observed in SZ individuals (42). Furthermore, some studies demonstrated that KATs expression/activity is increased under different inflammatory conditions (56)(57)(58)(59). Although there are no data linking inflammatory state to the expression/activity of the different isoforms of KATs, it could be speculated that the hypothesized inflammatory state may also explain the small but significant increased expression of KAT III, which does not normally make significant contribution to KYNA neosynthesis in the mammalian brain (23,60).…”

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

“…A previous study found that physical exercise may improve inflammatory responses by increasing KA production ( 16 ). Furthermore, KA has also been shown to improve mortality in a mouse model of sepsis by inhibiting neutrophil activity and reducing the expression of inflammatory factors ( 17 ). However, whether KA can inhibit macrophage pyroptosis and its underlying mechanism remain unclear.…”