Inflammatory response of microglial BV‐2 cells includes a glycolytic shift and is modulated by mitochondrial glucose‐regulated protein 75/mortalin

Abstract

Recent studies suggest a link between mitochondria and proinflammatory cytokine generation. We previously demonstrated that overexpression of mitochondrial chaperone glucose-regulated protein75 (Grp75/mortalin) protects mitochondria. In this study we investigated the modulation of the lipopolisaccharide (LPS)-induced inflammatory response of microglial BV-2 cells by Grp75. We demonstrate that LPS-induced activation promotes significant metabolic changes suppressing mitochondrial function and increasing glycolysis. Overexpression of Grp75 attenuates the LPS-induced oxidative and metabolic responses, and suppresses proinflammatory activation, which depends on both NF-κB activation and lactate. Thus overexpression of Grp75 provides a novel strategy to modulate proinflammatory cytokine production of relevance to inflammation-associated pathologies.

Mitochondrial ROS govern the LPS-induced pro-inflammatory response in microglia cells by regulating MAPK and NF-κB pathways

“…Other reports suggest that regulation of LPS-induced mitochondrial ROS is involved in the pro-inflammatory response of BV-2 microglia cells via NF-B activation [7,22]. We, therefore, examined whether mitochondrial ROS affect the LPS-induced MAPK and NF-B signal pathways by using Mito-TEMPO.…”

“…Apart from serving as an antimicrobial defense in microglia cells, ROS are key factors in immune cell signaling [15]. Mitochondrial ROS are implicated in the pro-inflammatory responses of microglia cells [7,22]. In addition, various treatments that induce mitochondrial ROS result in enhanced activation of inflammation transcription factors [6,8].…”

“…Although NADPH oxidase-derived ROS are regarded as important molecules governing microglial phagocytosis and/or MAPK activation [18], recent studies have suggested that mitochondrial ROS play an important role in modulating immunoreactions as part of the innate immune system [6,8,25]. Therefore, it is likely that neutralization of mitochondrial ROS or suppression of the redox pathway can alleviate inflammation [6,22]. However, the role of mitochondrial ROS production in microglial activation has yet to be fully elucidated.…”

Dual Role of Superoxide Dismutase 2 Induced in Activated Microglia

“…Therefore, the overall levels of ROS can be effectively reduced by eliminating superoxide. Activated microglia produce superoxide predominantly from NADPH oxidase, although ROS generation from mitochondria has also been reported (10,11). Of note, once ROS are generated anywhere within cells, further ROS generation is induced via uncoupling of the mitochondrial respiratory chain, known as ROS-induced ROS release (46).…”

“…Copper chloride has been shown to stimulate mitochondrial superoxide production in murine BV-2 microglial cells (10). Lipopolysaccharide (LPS), an endotoxin found in the outer membrane of Gram-negative bacteria, also elicits mitochondrial superoxide production, which is regulated by the mitochondrial chaperone glucose-regulated protein 75 (Grp75/mortalin) (11). Naik and Dixit (12) suggested that alterations in the redox environment of the plasma membrane could cause mitochondrial ROS formation.…”