Journal of neuroimmunology
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Cytokines, peptide hormones and neurotransmitters, as well as their receptors/ligands, are endogenous to the brain, endocrine and immune systems. These shared ligands and receptors are used as a common chemical language for communication within and between the immune and neuroendocrine systems. Such communication suggests an immunoregulatory role for the brain and a sensory function for the immune system. ⋯ Cytokines are chemical messengers that stimulate the HPA axis when the body is under stress or experiencing an infection. This review discusses current knowledge of cytokine signaling pathways in neuro-immune-endocrine interactions as viewed through the triplet HPA axis. In addition, we elaborate on HPA/cytokine interactions in oxidative stress within the context of nuclear factor-kappaB transcriptional regulation and the role of oxidative markers and related gaseous transmitters.
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The mechanisms underlying cell death following traumatic brain injury (TBI) are not fully understood. Apoptosis is believed to be one mechanism contributing to a marked and prolonged neuronal cell loss following TBI. Recent data suggest a role for Fas (APO-1, CD95), a type I transmembrane receptor glycoprotein of the nerve growth factor/tumor necrosis factor superfamily, and its ligand (Fas ligand, FasL) in apoptotic events in the central nervous system. ⋯ Furthermore, there was no correlation with two markers of immune activation (soluble interleukin-2 receptor and neopterin) in CSF. Maximal CSF levels of sFas correlated significantly (r(2)=0.8191, p<0.001) with the early peaks of neuron-specific enolase in CSF (a marker for neuronal cell destruction), indicating that activation of the Fas mediated pathway of apoptosis may be in part the direct result of the initial trauma. However, the prolonged elevation of sFas in CSF may be caused by the ongoing inflammatory response to trauma and delayed apoptotic cell death.
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Microglial cells are among the first and dominant cell types to respond to CNS injury. Following calcium influx, microglial activation leads to a variety of cellular responses, such as proliferation and release of cytotoxic and neurotrophic mediators. Allograft inflammatory factor-1, AIF-1 is a highly conserved EF-handed, putative calcium binding peptide, associated with microglia activation in the brain. ⋯ It appears that AIF-1+ microglia/macrophages are among the earliest cells to respond to spinal cord injury. Our results suggest a role of AIF-1 in the initiation of the early microglial response leading to activation and proliferation essential for the acute response to CNS injury. AIF-1 might modulate microgliosis influencing the efficacy of tissue debris removal, myelin degradation, recruitment of oligodendrocytes and re-organisation of the CNS architecture.
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Painful sensory neuropathy is a common and debilitating consequence of human immunodeficiency virus (HIV). The underlying causes of neuropathic pain are most likely not due to direct infection of the nervous system by active virus. The goal of this study was to determine whether epineural exposure to the HIV-1 envelope protein gp120 could lead to chronic painful peripheral neuropathy. ⋯ The gp120-exposed sciatic nerve exhibited early but transient pathology, notably axonal swelling and increased tumor necrosis factor alpha (TNF-alpha) within the nerve trunk. In contrast, intense astrocytic and microglial activation was observed in the spinal cord, and this gliosis persisted for at least 30 days following epineural gp120, in parallel with neuropathic pain behaviors. These findings demonstrate that limited peripheral nerve exposure to HIV protein can induce persistent painful sensory neuropathy that may be sustained and magnified by long-term spinal neuropathology.
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Tumor necrosis factor-alpha (TNF-alpha) is a key player in peripheral nerve injury. In the inflammatory chronic constriction injury (CCI) model of sciatic neuropathy, upregulation of TNF-alpha mRNA and protein at the site of nerve injury has been associated with pain. We now report the distribution of endogenous TNF-alpha protein and its receptors along normal and CCI-injured sciatic nerves, and within the corresponding lumbar dorsal root ganglia (DRG). ⋯ In animals with CCI neuropathy, uptake of biotinylated TNF-alpha by neuronal soma was inhibited. Instead, there was signal accumulation in the axons immediately distal to the DRG, and TNFRI and RII were increased at this same anatomic location. These findings highlight a dynamic process of TNF-alpha protein and receptor regulation throughout the peripheral neural axis that bears on both the normal function of DRG neurons and the pathogenesis of painful neuropathies.