Neuroscience
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Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). Despite intense investigations, little is known about its pathological mediators. Here, we report the marked upregulation of RANTES (regulated on activation, normal T cell expressed and secreted) and eotaxin, chemokines that are involved in T cell trafficking, in the serum of hemiparkinsonian monkeys. ⋯ Furthermore, the microglial upregulation of RANTES in the nigra of hemiparkinsonian monkeys could be involved in the altered adaptive immune response in the brain as we observed greater infiltration of CD8(+) T cells around the perivascular niche and deep brain parenchyma of hemiparkinsonian monkeys as compared to control. The treatment of hemiparkinsonian monkeys with NBD peptides decreased the microglial expression of RANTES and attenuated the infiltration of CD8(+) T cells in nigra. These results indicate the possible involvement of chemokine-dependent adaptive immune response in Parkinsonism.
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Peripheral nerves regenerate following injury due to the effective activation of the intrinsic growth capacity of the neurons and the formation of a permissive pathway for outgrowth due to Wallerian degeneration (WD). WD and subsequent regeneration are significantly influenced by various immune cells and the cytokines they secrete. Although macrophages have long been known to play a vital role in the degenerative process, recent work has pointed to their importance in influencing the regenerative capacity of peripheral neurons. In this review, we focus on the various immune cells, cytokines, and chemokines that make regeneration possible in the peripheral nervous system, with specific attention placed on the role macrophages play in this process.
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Recent research suggests a complex role for microglia not only in Parkinson's disease but in other disorders involving alpha-synuclein aggregation, such as multiple system atrophy. In these neurodegenerative processes, the activation of microglia is a common pathological finding, which disturbs the homeostasis of the neuronal environment otherwise maintained, among others, by microglia. The term activation comprises any deviation from what otherwise is considered normal microglia status, including cellular abundance, morphology or protein expression. ⋯ Microglia's behavior will therefore be a determinant on the disease's progression. For this reason we believe that the better understanding of microglia's response to alpha-synuclein pathological accumulation across brain areas and disease stages is essential to develop novel therapeutic tools for Parkinson's disease and other alpha-synucleinopathies. In this review we will revise the most recent findings and developments with regard to alpha-synuclein and microglia in Parkinson's disease.
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Tumor necrosis factor (TNF) is the prototypic pro-inflammatory cytokine. It is central to host defense and inflammatory responses but under certain circumstances also triggers cell death and tissue degeneration. Its pleiotropic effects often lead to opposing outcomes during the development of immune-mediated diseases, particularly those affecting the central nervous system (CNS). ⋯ Thus the roles of TNF signaling in the CNS shift from the conventional dichotomy of beneficial and deleterious, that mainly explain effects under pathological conditions, to incorporate a growing number of "essential" and "desirable" roles for TNF and its main cellular source in the CNS, microglia, under physiological conditions including regulation of neuronal activity and maintenance of myelin. An improved holistic view of TNF function in the CNS might better reconcile the expansive experimental data with stark clinical evidence that reduced functioning of TNF and its dominant pro-inflammatory receptor, TNFR1, are risk factors for the development of multiple sclerosis. It will also facilitate the safe translation of basic research findings from animal models to humans and propel the development of more selective anti-TNF therapies aimed at selectively inhibiting deleterious effects of this cytokine while maintaining its essential and desirable ones, in the periphery and the CNS.
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Repeated social defeat (RSD) in mice causes myeloid cell trafficking to the brain that contributes to the development of prolonged anxiety-like behavior. Myeloid cell recruitment following RSD occurs in regions where neuronal and microglia activation is observed. Thus, we hypothesized that crosstalk between neurons, microglia, and endothelial cells contributes to brain myeloid cell trafficking via chemokine signaling and vascular adhesion molecules. ⋯ While CXCL12 was unaffected by RSD, CCL2 expression was increased by six days of social defeat. Last, comparison between enriched CD11b(+) cells (microglia/macrophages) and enriched GLAST-1(+)/CD11b(-) cells (astrocytes) revealed RSD increased mRNA expression of IL-1β, CCL2, and CXCL2 in microglia/macrophages but not in astrocytes. Collectively, these data indicate that key mediators of leukocyte recruitment were increased in the brain vasculature following RSD in an exposure- and brain region-dependent manner.