Inflammatory Cytokines at the Summits of Pathological Signal Cascades in Brain Diseases

Departments of Pediatrics and Neurology and Neurological Sciences, Stanford University, Beckman Center for Molecular Medicine, Stanford, CA 94305-5316, USA.
Science Signaling (Impact Factor: 6.28). 01/2013; 6(258):pe3. DOI: 10.1126/scisignal.2003898
Source: PubMed


When considering the hierarchical organization of pathological signaling cascades in immunological disorders of the brain, certain cytokines might be considered pinnacles of pathophysiological importance, with their presence determining the appearance or the course of a particular disease. Interleukin-1 (IL-1), IL-6, IL-17, and tumor necrosis factor are critical for the pathogenesis of inflammation in specific brain disorders. Targeting these cytokines or their receptors can alter the course of several neurological diseases, but the effects may be beneficial or harmful.

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    • "An increasing number of studies have shown that one cause of a dysfunctional BBB is inflammatory cytokines. For example, tumor-necrosis factor í µí»¼ (TNFí µí»¼), interleukin-(IL-) 1í µí»½, and IL-17A have all been reported to loosen the BBB [5]. "
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    ABSTRACT: The central nervous system (CNS) is an immune-privileged environment protected by the blood-brain barrier (BBB), which consists of specific endothelial cells that are brought together by tight junctions and tight liner sheets formed by pericytes and astrocytic end-feet. Despite the BBB, various immune and tumor cells can infiltrate the CNS parenchyma, as seen in several autoimmune diseases like multiple sclerosis (MS), cancer metastasis, and virus infections. Aside from a mechanical disruption of the BBB like trauma, how and where these cells enter and accumulate in the CNS from the blood is a matter of debate. Recently, using experimental autoimmune encephalomyelitis (EAE), an animal model of MS, we found a "gateway" at the fifth lumber cord where pathogenic autoreactive CD4+ T cells can cross the BBB. Interestingly, this gateway is regulated by regional neural stimulations that can be mechanistically explained by the gate theory. In this review, we also discuss this theory and its potential for treating human diseases.
    Full-text · Article · Aug 2013 · Mediators of Inflammation
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    • "Thus, the stimulation or inhibition of cytolytic or regulatory arms through the release of chemokines or cytokines by atrocytes may result in markedly different outcomes that modulate immune responses in the brain. Targeting cytokines/chemokines or their receptors can alter the course of several neurological diseases, and the effects may be beneficial or harmful, depending on the particular situation (Steinman, 2013). Therefore, the study of the mechanisms underlying T-cell–astrocyte communication will be important for the design of therapeutic strategies for neurodegenerative disorders and brain tumors that show T-cell infiltration. "
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    ABSTRACT: The role of astrocytes in the immune-mediated inflammatory response in the brain is more prominent than previously thought. Astrocytes become reactive in response to neuro-inflammatory stimuli through multiple pathways, contributing significantly to the machinery that modifies the parenchymal environment. In particular, astrocytic signaling induces the establishment of critical relationships with infiltrating blood cells, such as lymphocytes, which is a fundamental process for an effective immune response. The interaction between astrocytes and T-cells involves complex modifications to both cell types, which undergo micro-anatomical changes and the redistribution of their binding and secretory domains. These modifications are critical for different immunological responses, such as for the effectiveness of the T-cell response, for the specific infiltration of these cells and their homing in the brain parenchyma, and for their correct apposition with antigen-presenting cells (APCs) to form immunological synapses (ISs). In this article, we review the current knowledge of the interactions between T-cells and astrocytes in the context of immune-mediated inflammation in the brain, based on the micro-anatomical imaging of these appositions by high-resolution confocal microscopy and three-dimensional rendering. The study of these dynamic interactions using detailed technical approaches contributes to understanding the function of astrocytes in inflammatory responses and paves the way for new therapeutic strategies.
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    ABSTRACT: This Focus Issue of Science Signaling, which complements the Science Special Issue on Inflammation, includes research that reveals regulators of a receptor implicated in an inflammatory bowel disease, as well as the contribution of a matrix metalloproteinase to skin inflammation. Perspectives discuss the role of proinflammatory cytokines in brain inflammatory disorders and the regulation of multiple types of cell death in tissues in response to proinflammatory factors. Together with content from the Science Signaling Archives, these articles underline the importance of understanding the basis of inflammatory responses that can both protect and harm the host.
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