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MKP1 reduces neuroinflammation via inhibiting endoplasmic reticulum stress and mitochondrial dysfunction
1Department of Neurosurgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
Abstract:
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.
Insights
MAP kinase phosphatase 1 (MKP1) protects against neuroinflammation by maintaining mitochondrial function and reducing cell death in microglia. It modulates endoplasmic reticulum stress and the MAPK-JNK pathway.
Area of Science:
- Neuroscience
- Cell Biology
- Immunology
Background:
- MAP kinase phosphatase 1 (MKP1) is an antiapoptotic protein supporting mitochondrial function.
- The specific role of MKP1 in neuroinflammation remains unclear.
- Microglia are key players in neuroinflammation and are susceptible to cell death.
Purpose of the Study:
- To investigate the influence of MKP1 in lipopolysaccharide (LPS)-induced neuroinflammation in BV-2 microglia.
- To determine if MKP1 mitigates BV-2 cell death by modulating endoplasmic reticulum (ER) stress and mitochondrial dysfunction.
- To elucidate the signaling pathways involved in MKP1's protective effects.
Main Methods:
- Utilized MKP1 adenovirus transfection in LPS-treated BV-2 microglia.
- Assessed cell viability, apoptosis, ER stress markers, calcium levels, and mitochondrial function.
- Analyzed the involvement of the mitogen-activated protein kinase-c-Jun N-terminal kinase (MAPK-JNK) pathway.
Main Results:
- LPS rapidly downregulated MKP1 expression in BV-2 cells.
- MKP1 overexpression reversed LPS-induced cell death and apoptosis.
- MKP1 alleviated ER stress, corrected calcium overload, and restored mitochondrial function.
- MKP1 inactivated the MAPK-JNK pathway, which was crucial for its protective effects.
Conclusions:
- MKP1 acts as a critical defender against neuroinflammation in microglia.
- MKP1 protects BV-2 cells by modulating ER stress and mitochondrial dysfunction.
- The protective mechanism of MKP1 is dependent on the inactivation of the MAPK-JNK pathway.
- MKP1 represents a potential therapeutic target for neuroinflammatory diseases.
