Nrf2 deficiency exacerbates PM2.5-induced olfactory bulb injury

Highlights: • Nrf2 deficiency exacerbates PM_2.5-induced olfactory bulb injury and activates microglia. • Nrf2 deficiency exacerbates PM_2.5-induced NF-κB activation in microglia of olfactory bulb. • Nrf2 deficiency exacerbates production of pro-inflammatory mediators by PM_2.5. • Nrf2 exerts a protective effect against PM_2.5-induced neurotoxicity via the NF-κB pathway. Recent studies have demonstrated that long-term exposure to fine particulate matter (PM_2.5) increases the risk of central nervous (CNS) diseases. As a basic region-leucine zipper (bZip) transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2) is essential for protection against chemically induced oxidative stress to restore cellular redox balance. However, the impact of Nrf2 on the neurotoxic effects of PM_2.5 remains to understand. In this study, we exposed wild-type (WT) and Nrf2 knockout (Nrf2^−/−) mice to 1 mg/kg PM_2.5 or deionized water by intranasal instillation for 28 days. After PM_2.5 exposure, Nrf2^−/− mice exhibited severe nerve injury in olfactory bulb (OB) of mice. In PM_2.5-treated OBs, Nrf2 deficiency resulted in lower levels of antioxidant enzymes, greater induction of oxidative stress, microglia activation, inflammation and nuclear factor kappa B (NF-κB) activation compared to the OBs of WT mice. In PM_2.5-treated BV2 cells, inhibition of Nrf2 activity significantly decreased cell viability and increased the intracellular reactive oxygen species (ROS) generation and nuclear factor kappa B (NF-κB) phosphorylation. Taken together, our results provide the role Nrf2-reuglated antioxidant and cytoprotective enzymes in protective responses to PM_2.5-induced neurotoxicity. Our findings suggest Nrf2-mediated defenses against oxidative stress will help develop new strategies for the prevention and treatment of diseases associated with airborne pollution.