MKP1 reduces neuroinflammation via inhibiting endoplasmic reticulum stress and mitochondrial dysfunction

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. K E Y W O R D S BV-2 cells, ER stress, LPS, mitochondrial damage, MKP1, neuroinflammation

PTP1B inhibitor alleviates deleterious microglial activation and neuronal injury after ischemic stroke by modulating the ER stress-autophagy axis via PERK signaling in microglia

“…ER stress has been demonstrated to be a critical event to cause cerebral IR injury, and recent studies showed extensive involvement of ER stress in microglial activation to participate in diverse cerebral injuries including Alzheimer's Disease [51], spinal cord injury [52] and LPS/cocaine-induced neuroinflammation [17,53]. PTP1B was reported to be a positive regulator of ER stress [15,16], yet its role in microglial ER stress has not been well illustrated.…”

[Retracted] MKP‐1 Overexpression Reduces Postischemic Myocardial Damage through Attenuation of ER Stress and Mitochondrial Damage

“…These results are consistent with previous studies. For example, MKP-1 deletion caused mitochondrial damage, resulting in decreased insulin release in obesity [41,61]. In diabetic rats, MKP-1 overexpression improved cardiac performance by promoting mitochondrial metabolism [62].…”

“…Calcium signal transduction, lipid transport, and energy metabolism are regulated by mitochondria-ER interactions, although detailed molecular patterns have not been identified [40]. Recent studies have identified mitogen-activated protein kinase (MAPK) phosphatase 1 (MKP-1) as a novel regulator of ER function and mitochondrial homeostasis in neuroinflammation [41] and diabetic nephropathy [42]. In this study, we asked whether MKP-1 affects myocardial postischemia damage through regulating mitochondrial homeostasis and ER function.…”

PTP1B inhibitor alleviates deleterious microglial activation and neuronal injury after ischemic stroke by modulating ER stress-autophagy axis via PERK signaling in microglia

“…Several studies have reported the role of PTP1B as a positive regulator of microglial activation, and inhibition or deficiency of PTP1B effectively attenuated neuroinflammation [11,49,50]. ER stress has been demonstrated to be a critical event to cause cerebral IR injury, and recent studies showed extensive involvement of ER stress in microglial activation to participate in diverse cerebral injuries including Alzheimer's Disease [51], spinal cord injury [52] and LPS/cocaine-induced neuroinflammation [17,53]. PTP1B was reported to be a positive regulator of ER stress [15,16], yet its role in microglial ER stress has not been well illustrated.…”