Inhibition of MSK1 Promotes Inflammation and Apoptosis and Inhibits Functional Recovery After Spinal Cord Injury

Abstract

Mitogen- and stress-activated kinase (MSK) 1 is a nuclear serine/threonine kinase. In the central nervous system, it plays an important role in regulating cell proliferation and neuronal survival; it is also involved in astrocyte inflammation and the inhibition of inflammatory cytokine production. However, its specific role in spinal cord injury is not clear. Here, we aimed to elucidate this role using an in vivo animal model. In this study, we found that MSK1 is gradually decreased, starting 1 day after spinal cord injury and to its lowest level 3 days post-injury, after which it gradually increased. To further investigate the possible function of MSK1 in spinal cord injury, we interfered with its expression by utilizing a small interfering RNA (siRNA)-encoding lentivirus, which was injected into the injured spinal cord to inhibit local expression. After MSK1 inhibition, we found that the expression of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β were increased. Moreover, the expression of IL-10 was decreased. In addition, neuronal apoptotic cells were increased significantly and expression of the apoptosis-related protein caspase-3 was also increased. Ultrastructural analysis of nerve cells also revealed typical neuronal apoptosis and severe neuronal damage. Finally, we found that hindlimb motor function decreased significantly with MSK1 knockdown. Therefore, our findings suggest that the inhibition of this protein promotes inflammatory responses and apoptosis and suppresses functional recovery after spinal cord injury. MSK1 might thus play an important role in repair after spinal cord injury by regulating inflammation and apoptosis. Electronic supplementary material The online version of this article (10.1007/s12031-019-01298-9) contains supplementary material, which is available to authorized users.

Mettl14-mediated m6A modification modulates neuron apoptosis during the repair of spinal cord injury by regulating the transformation from pri‐mir‐375 to miR-375

“…Apoptosis plays an important role in the repair of SCI [21]. Then, to explore whether Mettl14 expression also affects the apoptosis of cells in SCI, we detected the apoptosis of neurons in spinal cord tissues of rats at the 30th day, and caspase-3 expression.…”

The role of cigarette smoke-induced epigenetic alterations in inflammation

“…These results indicate a promoting effect of MSK1 on inflammation. However, Zhong et al [165] put forward a different opinion, suggesting that MSK1 is negatively correlated with astrocyte inflammation and can inhibit inflammatory cytokine production. They showed that MSK1 inhibition promoted the expression of TNF - α , IL - 6 , IL - 10 , and IL - 1β .…”

Inflammatory response and oxidative stress attenuated by sulfiredoxin‑1 in neuron‑like cells depends on nuclear factor erythroid‑2‑related factor 2

“…SRX1 expression levels are downregulated in PC12 cells stimulated with LPS. Subsequently, in vitro experiments were performed using the PC12 cell line, a common cell model used for researching neurobiological events, including SCI (22)(23)(24)(25). A range of concentrations of LPS (0.625-5 µg/ml) were used to stimulate PC12 cells for 18 h as previously described (26) and the viability of PC12 cells was subsequently determined.…”

“…Rat pheochromocytoma PC12 cells (China Center for Type Culture Collection) were cultured in DMEM (Hyclone; Cytiva), supplemented with 10% FBS (Hyclone; Cytiva), and maintained at 37˚C under humid conditions with 5% CO 2 and 95% air. For differentiation, PC12 cells were treated with 50 ng/ml nerve growth factor (Sigma-Aldrich; Merck KGaA) every other day for 6 days at 37˚C, which is a widely used method for the in vitro study of nervous system diseases, including SCI (22)(23)(24)(25).…”