Ischemic stroke, caused by a sudden disruption of blood flow to the brain, is a leading cause of death and exerts a heavy burden on both patients and public health systems. Currently available treatments for ischemic stroke are very limited and are not feasible in many patients due to strict time windows required for their administration. Thus, novel treatment strategies are keenly required. T cells, which are part of the adaptive immune system, have gained more attention for its effects in ischemic stroke. Both preclinical and clinical studies have revealed the conflicting roles for T cells in post-stroke inflammation and as potential therapeutic targets. This review summarizes the mediators of T cell recruitment, as well as the temporal course of its infiltration through the blood-brain-barrier, choroid plexus, and meningeal pathways. Furthermore, we describe the mechanisms behind the deleterious and beneficial effects of T cells in the brain, in both antigen-dependent and antigen-independent manners, and finally we specifically focus on clinical and preclinical studies that have investigated T cells as potential therapeutic targets for ischemic stroke.

Ischemic stroke is caused by insufficient cerebrovascular blood and oxygen supply. It is a major contributor to death or disability worldwide and has become a heavy societal and clinical burden. To date, effective treatments for ischemic stroke are limited, and innovative therapeutic methods are urgently needed. Hypoxia inducible factor-1α (HIF-1α) is a sensitive regulator of oxygen homeostasis, and its expression is rapidly induced after hypoxia/ischemia. It plays an extensive role in the pathophysiology of stroke, including neuronal survival, neuroinflammation, angiogenesis, glucose metabolism, and blood brain barrier regulation. In addition, the spatiotemporal expression profile of HIF-1α in the brain shifts with the progression of ischemic stroke; this has led to contradictory findings regarding its function in previous studies. Therefore, unveiling the Janus face of HIF-1α and its target genes in different type of cells and exploring the role of HIF-1α in inflammatory responses after ischemia is of great importance for revealing the pathogenesis and identifying new therapeutic targets for ischemic stroke. Herein, we provide a succinct overview of the current approaches targeting HIF-1α and summarize novel findings concerning HIF-1α regulation in different types of cells within neurovascular units, including neurons, endothelial cells, astrocytes, and microglia, during the different stages of ischemic stroke. The current representative translational approaches focused on neuroprotection by targeting HIF-1α are also discussed.

No abstract

The COP9 signalosome (CSN) is an evolutionarily conserved multi-subunit protein complex, which controls protein degradation through deneddylation and inactivation of cullin-RING ubiquitin E3 ligases (CRLs). Recently, the CSN complex has been linked to the NF-κB signaling pathway due to its association with the IKK complex. However, how the CSN complex is regulated in this signaling pathway remains unclear. Here, we have carried out biochemical experiments and confirmed the interaction between the CSN and IKK complexes. In addition, we have determined that overexpression of IKKα or IKKβ leads to enhanced phosphorylation of CSN5, the catalytic subunit for CSN deneddylase activity. Mutational analyses have revealed that phosphorylation at serine 201 and threonine 205 of CSN5 impairs CSN-mediated deneddylation activity in vitro. Interestingly, TNF-α treatment not only enhances the interaction between CSN and IKK, but also induces an IKK-dependent phosphorylation of CSN5 at serine 201, linking CSN to TNF-α signaling through IKK. Moreover, TNF-α treatment affects CSN interaction network globally, especially the associations of CSN with the proteasome complex, eukaryotic translation