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MAP kinase phosphatase 1 (MKP1) has been identified as an antiapoptotic protein via sustaining mitochondrial function. However, the role of MKP1 in neuroinflammation has not been fully understood. The aim of this study is to figure out the influence of MKP1 in lipopolysaccharide (LPS)‐treated microglia BV‐2 cells and investigate whether MKP1 reduces BV‐2 cell death via modulating endoplasmic reticulum (ER) stress and mitochondrial dysfunction. The results of this study demonstrated that MKP1 was rapidly downregulated after exposure to LPS. However, the transfection of MKP1 adenovirus could reverse cell viability and attenuate LPS‐mediated BV‐2 cell apoptosis. Mechanistically, MKP1 overexpression alleviated ER stress and corrected LPS‐induced calcium overloading. Besides, MKP1 adenovirus transfection also reversed mitochondrial bioenergetics, maintained mitochondrial membrane potential, and blocked mitochondria‐initiated apoptosis signals. Furthermore, we found that MKP1 overexpression is associated with inactivation of mitogen‐activated protein kinase–c‐Jun N‐terminal kinase (MAPK–JNK) pathway. Interestingly, the activation of MAPK–JNK pathway could abolish the protective effects of MKP1 on BV‐2 cells survival and mitochondrial function in the presence of LPS. Altogether, our results identified MKP1 as a primary defender of neuroinflammation via modulating ER stress and mitochondrial function in a manner dependent on MAPK–JNK pathway. These findings may open a new window for the treatment of neuroinflammation in the clinical setting. [ABSTRACT FROM AUTHOR]

Mitochondrial dysfunction has been found to be associated with neuronal inflammation; however, no effective drug is available to attenuate neuroinflammation via sustaining mitochondrial function. In the current study, experiments were performed to understand the beneficial effects of mitochonic acid 5 (MA‐5) on tumor necrosis factor‐α (TNF‐α)‐mediated neuronal injury and mitochondrial damage. Our data illustrated that MA‐5 pretreatment reduced inflammation response induced by TNF‐α in CATH.a cells. Molecular investigations demonstrated that MA‐5 pretreatment repressed oxidative stress, inhibited endoplasmic reticulum stress, sustained cellular energy metabolism, and blocked cell apoptosis induced by TNF‐α stress. Further, we found that MA‐5 treatment elevated the expression of Sirtuin 3 (Sirt3) and this effect was dependent on the activation of AMP‐activated protein kinase (AMPK) pathway. Blockade of AMPK abolished the promotive action of MA‐5 on Sirt3 and thus mediated mitochondrial damage and cell death. Besides, we also found that MA‐5 treatment augmented Parkin‐related mitophagy and increased mitophagy promoted CATH.a cells survival via improving mitochondrial function. Knockdown of Parkin abolished the beneficial action of MA‐5 on mitochondrial homeostasis and CATH.a cell survival. Altogether, our results confirm that MA‐5 is an effective drug to attenuate neuroinflammation via sustaining mitochondrial damage and promoting CATH.a cell survival. The protective action of MA‐5 on neuronal damage is associated with Parkin‐related mitophagy and the activation of AMPK–Sirt3 pathways. [ABSTRACT FROM AUTHOR]