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Abstract Activating transcription factor 2 (ATF2), a member of the alkaline-leucine zipper family, is widely expressed in various tissues, and reportedly involved in inflammatory responses to various irritates, but its role in the central nervous system (CNS) remains unclear. This study aimed to investigate the expression and biological function of ATF2 in CNS inflammation. Utilizing the LPS-induced neuroinflammation model on mice, we first found ATF2 up-regulation and its co-localization with microglia in inflamed mice brain. In vitro, we revealed an increased expression, phosphorylation, and nuclear accumulation of ATF2 in LPS-treated BV2 microglia cells. Inhibiting ATF2 significantly decreased the expression of pro-inflammatory factors in LPS-treated microglia, and alleviated neuronal apoptosis induced by the conditioned medium of activated microglia. Knocking down TRAF6, an important adaptor of the TLR4/MAPK/NF-κB signaling pathway, suppressed the LPS-induced ATF2 expression and phosphorylation, accompanied by the decreased p38/JNK phosphorylation, in microglia. Blocking p38 or JNK signaling pathway by the specific inhibitors reversed the TRAF6-overexpression mediated ATF2 activation. Taken together, our data first proved the pro-inflammatory function of ATF2 in microglia, and suggested that the TRAF6-JNK/p38-ATF2 axis might promote microglial inflammatory activation and thus aggravate neuronal injury in brain, which might become a potential therapeutic target for CNS diseases. Highlights • LPS induces ATF2 expression and activation in microglia both in vivo and in vitro. • ATF2 promotes microglia activation and the subsequent neuronal apoptosis in vitro. • TRAF6 positively regulates ATF2 activation in LPS-treated microglia. • The TRAF6-p38/JNK-ATF2 axis contributes to microglia-mediated neuroinflammation. [ABSTRACT FROM AUTHOR]

Glial scar formation derived from astrocyte proliferation and migration influences the functional recovery after spinal cord injury. Cyclin-dependent kinase inhibitor p27 kip1 , whose activity is closely related to its phosphorylation state, reportedly regulates astrocyte proliferation and migration. In this study, we reported that p27 Kip1 undergoes O-GlcNAc modification at Ser 2, Ser 110 and Thr 197. Inhibiting O-GlcNAcylation on Ser 2 by gene mutation (S2A) attenuated the phosphorylation of Ser 10, and vice versa. Interestingly, compared with wild type p27 Kip1 , S2A p27 Kip1 displayed a decreased interaction with CRM1 and reduced nuclear export following serum starvation and release. In addition, the interaction between stathmin and S2A p27 Kip1 was also decreased. Cytoskeletal proteins microtubules appeared high density in astrocytes transfected with S2A p27 Kip1 especially at the leading edge of the scratch wound. Accordingly, scratch-wound assay revealed that the motility of astrocytes transfected with S2A p27 Kip1 was faster than that of control. Finally, we injected lentiviral vectors immediately after spinal cord contusion, and found the lesion volume of the rat injected with S2A p27 Kip1 was smaller than that of rat injected with wild type p27 Kip1 . Besides, the BBB and CBS behavioral tests showed greater functional recovery in S2A p27 Kip1 treated rats. Taken together, our findings revealed a novel function of O-GlcNAc modification of p27 Kip1 in mediating astrocytes migration and functional recovery after spinal cord contusion. [ABSTRACT FROM AUTHOR]