Apoptosis In Neuroinflammation Research Articles

Upregulation of PSMB4 is Associated with the Necroptosis after Spinal Cord Injury.

Spinal cord injury (SCI) is one of the most common and severe complications in spine injury. It is difficult to prevent cell necroptosis and promote the survival of residual neurons after SCI. Proteasome beta-4 subunit (PSMB4) is the first proteasomal subunit with oncogenic properties promoting cancer cell survival and tumor growth in vivo, and our previous study showed that PSMB4 is significantly associated with neuronal apoptosis in neuroinflammation. However, PSMB4 function in the necroptosis after SCI is unkown. RIP3, a key regulatory factor of necroptosis, correlates with the induction of necroptosis in various types of cells and signaling pathway. Upregulation of the RIP3 expression may play a role as a novel molecular mechanism in secondary neural tissue damage following SCI. In this study, we established an acute spinal cord contusion injury model in adult rats to investigate the potential role of PSMB4 during the pathological process of SCI. We found PSMB4 expression was significantly up-regulated 3 days after injury by western blot and immunohistochemical staining. Double immunofluorescent staining indicated obvious changes of PSMB4 expression occurred in neurons. Significant up-regulation of PSMB4 expression was observed in Rip3 positive neurons at 3 days after SCI, which indicated that PSMB4 might play a vital role in the regulation of Rip3. Overexpress and knockdown PSMB4 could intervene the RIP3 and Mixed lineage kinase domain-like protein (MLKL) pathway in Tumor necrosis factor-α (TNF-α) induced necroptosis cell model. Based on our experimental data, we boldly conclude that PSMB4 is associated with RIP3 involved necroptosis after SCI.

Up-regulation of PSMB4 is associated with neuronal apoptosis after neuroinflammation induced by lipopolysaccharide.

Proteasomes are major intracellular extralysosomal organelle for protein degradation and a central source of antigenic peptides in the endogenous pathway. Proteasome beta-4 subunit (PSMB4) was recently identified as potential cancer driver genes in several tumors. However, information regarding its regulation and possible function in the central nervous system is still limited. The present study was designed to elucidate dynamic changes in PSMB4 expression and distribution in the cerebral cortex in a lipopolysaccharide (LPS)-induced neuroinflammation rat model. It was found that PSMB4 expression was increased significantly in apoptotic neurons in the brain cortex after LPS injection. Moreover, there was a concomitant up-regulation of active caspase-3, cyclin D1, and CDK4 in vivo and vitro studies. In addition, these three proteins in cortical primary neurons were decreased after knocking down PSMB4 by siRNA. Collectively, these results suggested that PSMB4 may be involved in neuronal apoptosis in neuroinflammation after LPS injection.

Up-regulation of podoplanin involves in neuronal apoptosis in LPS-induced neuroinflammation.

Podoplanin (PDPN) is a mucin-type transmembrane sialoglycoprotein expressed in multiple tissues in adult animals, including the brain, lungs, kidney, and lymphoid organs. Studies of this molecule have demonstrated its great importance in tumor metastasis, platelet aggregation, and lymphatic vessel formation. However, information regarding its regulation and possible function in the central nervous system is still limited. In this study, we performed a neuroinflammatory model by lipopolysaccharide (LPS) lateral ventral injection in adult rats and detected increased expression of PDPN in the brain cortex. Immunofluorescence indicated that PDPN was located in the neurons, but not astrocytes. Moreover, there was a concomitant up-regulation of active caspase-3, cyclin D1, and CDK4 in vivo and vitro studies. In addition, the expression of these three proteins in cortical primary neurons was decreased after knocking down PDPN by siRNA. Collectively, all these results suggested that the up-regulation of PDPN might be involved in neuronal apoptosis in neuroinflammation after LPS injection.

Up-regulation of SGTB is associated with neuronal apoptosis after neuroinflammation induced by lipopolysaccharide

SGTB (Small glutamine-rich tetratricopeptide repeat (TPR)-containing, β) plays a critical role in protein-protein interactions. The interaction between SGTB and heat shock cognate protein (Hsc70)/heat shock protein (Hsp70) has aroused much attention in recent years. The present study was designed to elucidate dynamic changes in SGTB expression and distribution in the cerebral cortex in a lipopolysaccharide (LPS)-induced neuroinflammation rat model. It was found that SGTB expression was increased significantly in apoptotic neurons after LPS injection. The result of our in vitro study suggested that SGTB up-regulation might be associated with neuronal apoptosis after H2O2 challenge. In addition, silencing of SGTB in cultured PC12 (Pheochromocytoma) by siRNA indicated that SGTB was required for neuronal apoptosis induced by oxidative stress. Our finding about the cellular signal pathway may provide a new strategy against neuronal apoptosis in neuroinflammation in CNS.

Glucocorticoid-Induced Apoptosis in Animal Models of Multiple Sclerosis

Glucocorticoids (GCs) are highly potent anti-inflammatory and immunosuppressive agents. They exert influence on many cell types of the immune system and impact a plethora of processes such as cytokine production, leukocyte differentiation, migration and adhesion, apoptosis induction, and changes in morphology. Those that are most relevant for the modulation of neuroinflammatory diseases, however, are still under debate. In this review, we will elaborate on how GCs impact inflammatory responses in general and revisit the ambivalent role that apoptosis plays in animal models of multiple sclerosis. Furthermore, we will discuss arguments that speak in favor or against an essential function of GC-induced apoptosis in neuroinflammation. We anticipate that a better knowledge of the mechanisms that GCs employ will eventually find its way into clinical practice for the future benefit of afflicted patients.

Apoptosis Inhibition Can Be Threatening in Aβ-Induced Neuroinflammation, Through Promoting Cell Proliferation

Neuronal apoptosis in neurodegenerative diseases is correlated with inflammatory reactions. The beneficial or detrimental role of apoptosis in neuroinflammation is unclear. In this study, we injected β-amyloid peptide into the rat cortex for induction of neuroinflammation in hippocampus. We observed an increase in TNF-α as an inflammatory cytokine and caspase3 and TUNEL-positive cells as apoptotic marker. As far as ability of TNF-α to induce apoptosis or activate NF-kβ, the question is what will happen if the balance between two pathways is disturbed by inhibition of apoptosis. Using caspase inhibitors, we inhibited apoptosis and assessed NF-kβ, Hsp 70 (a hallmark of cancer), cmyc (proto-oncogene) and p53 (tumor suppressor protein). There was an unexpected decrease in NF-kβ while Hsp70 and cmyc upregulated and p53 decreased. These results imply that inhibition of apoptosis due to increased susceptibility to abnormal mitosis may not provide a reliable strategy for treatment of neuroinflammatory diseases.

The role of apoptosis in neuroinflammation.

Inflammatory diseases of the central nervous system (CNS) play a major role in clinical neurology. It is currently under debate whether inflammatory processes determine the outcome in, for example, brain injury (Woiciechowsky et al. 1998) and cerebral ischemia (Dirnagl et al. 1999). The classical and most demanding acute inflammatory disease of the CNS is bacterial meningitis which still displays a mortality rate of about 20%, despite effective antibiotic treatment (Schuchat et al. 1997). The functional outcome of bacterial meningitis regarding long-term sequelae is dictated by neuronal injury that leads to seizures, paralysis, and cognitive deficits in survivors. The most common chronic inflammatory disease of the CNS in Northern America and Europe, which causes prolonged and severe disability in young adults, is multiple sclerosis (MS). MS is thought to be an autoimmune disorder with demyelination and axonal pathology leading to clinical symptoms (Noseworthy et al. 2000). The pathogenesis in both bacterial meningitis and multiple sclerosis has not been completely elucidated, and therapies are still inefficient despite the progress made thus far. The heterogeneous clinical course of both meningitis and multiple sclerosis requires individual treatment. Since overall therapeutic options are still lacking, clinical and experimental approaches have been aimed towards identifying genes to advance pathogenetic explanation, discover predisposing parameters for various forms of the disease, and elicit suitable therapeutic strategies.