Abstract
Reactive oxygen species (ROS) production by activation of microglia is considered to be a major cause of neuronal dysfunction, which can lead to damage and death through direct oxidative damage to neuronal macromolecules or derangement of neuronal redox signaling circuits. BAP31, an integral ER membrane protein, has been defined as a regulatory molecule in the CNS. Our latest studies have found that BAP31 deficiency leads to activation of microglia. In this study, we discovered that BAP31 deficiency upregulated LPS-induced superoxide anion production in BV2 cells and mice by upregulating the expression level of p22phox and by inhibiting the activation of Nrf2-HO-1 signaling. Knockdown of p22phox/keap1 or use of an NADPH oxidase inhibitor (apocynin) reversed the production of superoxide anion and inflammatory cytokines, which then reduced neuronal damage and death in vitro and in vivo. These results suggest that BAP31 deficiency contributes to microglia-related superoxide anion production and neuroinflammation through p22phox and keap1. Furthermore, the excess superoxide anion cooperated with inflammatory cytokines to induce the damage and death of neurons. Thus, we determined that BAP31 is an important regulator in superoxide anion production and neuroinflammation, and the downstream regulators or agonists of BAP31 could therefore be considered as potential therapeutic targets in microglial-related superoxide anion production and neuroinflammation.
Highlights
Neurodegenerative diseases including Alzheimer’s disease (AD), Parkinson’s disease (PD), and multiple sclerosis (MS) are characterized by oxidative damage, chronic neuroinflammation, neuronal degeneration, and death in specific regions of the central nervous system (CNS) [1,2,3]
In the Nitroblue Tetrazolium (NBT) assay, superoxide anion production increased from 2:31 ± 0:09-fold to 3:11 ± 0:14 -fold (Figures 2(b) and 2(c)), Fð1,8Þ = 65:87, p < 0:001; DHE staining showed that intracellular superoxide anion significantly increased from 2:34 ± 0:10-fold to 3:28 ± 0:30-fold, Fð1,8Þ = 91:57, p < 0:001; and intracellular H2O2 significantly increased from 1:75 ± 0:18-fold to 2:65 ± 0:32-fold (Figure 2(d)), Fð1,12Þ = 45:17, p < 0:001
The results showed that the protein level of keap1 was significantly increased from 1:02 ± 0:15-fold to 3:21 ± 0:19-fold, p < 0:001, whereas the Nuclear factor erythroid 2-related factor 2 (Nrf2) protein was not influenced by the deficiency of B cell receptor-associated protein 31 (BAP31); after LPS stimulation, the protein level increased, but BAP31-deficient cells had a low level of Nrf2 compared with scramble cells (Figures 1(e) and 1(f)), Fð1,12Þ = 21:85, p < 0:001
Summary
Neurodegenerative diseases including Alzheimer’s disease (AD), Parkinson’s disease (PD), and multiple sclerosis (MS) are characterized by oxidative damage, chronic neuroinflammation, neuronal degeneration, and death in specific regions of the central nervous system (CNS) [1,2,3]. ROS are wellknown stress signaling molecules in cells, and can be increased dramatically by environmental stress and disease [4]. Since the effects of oxidative stress are widespread and the brain has low antioxidant capacities, neurons are vulnerable to oxidative damage induced by excess superoxide anion. Superoxide anion production by microglia is considered to be a major cause of neuronal dysfunction, damage, and death through direct oxidative damage to neuronal macromolecules or derangement of neuronal redox signaling circuits, and the ROS-amplified proinflammatory response in microglia drives neuropathology [5, 6]
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