Nrf2 mitigates prolonged PM2.5 exposure-triggered liver inflammation by positively regulating SIKE activity: Protection by Juglanin

Air pollution containing particulate matter (PM) less than 2.5 μm (PM2.5) plays an essential role in regulating hepatic disease. However, its molecular mechanism is not yet clear, lacking effective therapeutic strategies. In this study, we attempted to investigate the effects and mechanisms of PM2.5 exposure on hepatic injury by the in vitro and in vivo experiments. At first, we found that PM2.5 incubation led to a significant reduction of nuclear factor erythroid-derived 2-related factor 2 (Nrf2), along with markedly reduced expression of different anti-oxidants. Notably, suppressor of IKKε (SIKE), known as a negative regulator of the interferon pathway, was decreased in PM2.5-incubated cells, accompanied with increased activation of TANK-binding kinase 1 (TBK1) and nuclear factor-κB (NF-κB). The in vitro studies showed that Nrf2 positively regulated SIKE expression under the conditions with or without PM2.5. After PM2.5 treatment, Nrf2 knockdown further accelerated SIEK decrease and TBK1/NF-κB activation, and opposite results were observed in cells with Nrf2 over-expression. Subsequently, the gene loss- and gain-function analysis demonstrated that SIKE deficiency further aggravated inflammation and TBK1/NF-κB activation caused by PM2.5, which could be abrogated by SIKE over-expression. Importantly, SIKE-alleviated inflammation was mainly dependent on TBK1 activation. The in vivo studies confirmed that SIKE- and Nrf2-knockout mice showed significantly accelerated hepatic injury after long-term PM2.5 exposure through reducing inflammatory response and oxidative stress. Juglanin (Jug), mainly isolated from Polygonum aviculare, exhibits anti-inflammatory and anti-oxidant effects. We found that Jug could increase Nrf2 activation, and then up-regulated SIKE in cells and liver tissues, mitigating PM2.5-induced liver injury. Together, all these data demonstrated that Nrf2 might positively meditate SIKE to inhibit inflammatory and oxidative damage, ameliorating PM2.5-induced liver injury. Jug could be considered as an effective therapeutic strategy against this disease by improving Nrf2/SIKE signaling pathway.
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Highlights • PM2.5 incubation inhibits Nrf2 and SIKE activation in vitro. • Nrf2 positively regulates SIKE expression in PM2.5-incubated cells. • SIKE-regulated inflammatory response requires TBK1 blockage in PM2.5-treated cells. • Juglanin treatment suppresses inflammation in PM2.5-incubated cells through increasing SIKE expression.