Cardona, A. E. et al. Control of microglial neurotoxicity by the fractalkine receptor. Nature Neurosci. 9, 917-924

Neuroinflammation Research Center and Department of Neurosciences, Lerner Research Institute, Cleveland, Ohio 44195, USA.
Nature Neuroscience (Impact Factor: 16.1). 08/2006; 9(7):917-24. DOI: 10.1038/nn1715
Source: PubMed

ABSTRACT Microglia, the resident inflammatory cells of the CNS, are the only CNS cells that express the fractalkine receptor (CX3CR1). Using three different in vivo models, we show that CX3CR1 deficiency dysregulates microglial responses, resulting in neurotoxicity. Following peripheral lipopolysaccharide injections, Cx3cr1-/- mice showed cell-autonomous microglial neurotoxicity. In a toxic model of Parkinson disease and a transgenic model of amyotrophic lateral sclerosis, Cx3cr1-/- mice showed more extensive neuronal cell loss than Cx3cr1+ littermate controls. Augmenting CX3CR1 signaling may protect against microglial neurotoxicity, whereas CNS penetration by pharmaceutical CX3CR1 antagonists could increase neuronal vulnerability.

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    • "This was followed soon after with creation of a Cx3cr1 Gfp/Gfp mouse (Jung et al., 2000), which not only deleted Cx3cr1 but also allowed for clear identification of CX3CR1 in microglial cells (Cardona et al., 2006; Jung et al., 2000). Indeed, microglial cells from the Cx3cr1 Gfp/Gfp mice produced higher levels of IL-1b in response to LPS (Cardona et al., 2006; Rogers et al., 2011). 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was originally synthesized as a by-product in the synthesis of a meperidine analog, desmethylprodine, in the late 1970s. "
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    ABSTRACT: Immunotoxicology assessments have historically focused on the effects that xenobiotics exhibit directly on immune cells. These studies are invaluable as they identify immune cell targets and help characterize mechanisms and/or adverse outcome pathways of xenobiotics within the immune system. However, leukocytes can receive environmental cues by cell-cell contact or via released mediators from cells of organs outside of the immune system. These organs include, but are not limited to, the mucosal areas such as the lung and the gut, the liver, and the central nervous system. Homeostatic perturbation in these organs induced directly by toxicants can initiate and alter the outcome of local and systemic immunity. This review will highlight some of the identified nonimmune influences on immune homeostasis and provide summaries of how immunotoxic mechanisms of selected xenobiotics involve nonimmune cells or mediators. Thus, this review will identify data gaps and provide possible alternative mechanisms by which xenobiotics alter immune function that could be considered during immunotoxicology safety assessment. © The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail:
    Toxicological Sciences 06/2015; 145(2):214-32. DOI:10.1093/toxsci/kfv060 · 3.85 Impact Factor
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    • "the expression for common macrophage or DC markers , we compared both CD11c - positive populations of the brain to CD11c - positive populations of peripheral organs and found that CD11c - positive microglia contain a higher percentage of cells express - ing CX3CR1 and F4 / 80 , which are known as markers for res - ident macrophages and microglia ( Cardona et al . , 2006 ; Carson et al . , 1998 ; Harrison et al . , 1998 ; Jung et al . , 2000 ; Lewis et al . , 2011 ; Niess , 2005 ; Prinz et al . , 2011 ; Wlodarc - zyk et al . , 2014 ) . Further , in direct comparison to liver - , lung - and spleen - derived CD11c - positive cells , CD11c - positive microglia and brain macrophages showed significantly low"
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    ABSTRACT: The brain's immune privilege has been also attributed to the lack of dendritic cells (DC) within its parenchyma and the adjacent meninges, an assumption, which implies maintenance of antigens rather than their presentation in lymphoid organs. Using mice transcribing the green fluorescent protein under the promoter of the DC marker CD11c (itgax), we identified a juxtavascular population of cells expressing this DC marker and demonstrated their origin from bone marrow and local microglia. We now phenotypically compared this population with CD11c/CD45 double-positive cells from lung, liver, and spleen in healthy mice using seven-color flow cytometry. We identified unique, site-specific expression patterns of F4/80, CD80, CD86, CX3CR1, CCR2, FLT3, CD103, and MHC-II. Furthermore, we observed the two known CD45-positive populations (CD45(high) and CD45(int) ) in the brain, whereas liver, lung, and spleen exhibited a homogeneous CD45(high) population. CD11c-positive microglia lacked MHC-II expression and CD45(high) /CD11c-positive cells from the brain have a lower percentage of MHC-II-positive cells. To test whether phenotypical differences are fixed by origin or specifically develop due to environmental factors, we transplanted brain and spleen mononuclear cells on organotypic slice cultures from brain (OHSC) and spleen (OSSC). We demonstrate that adaption and ramification of MHC-II-positive splenocytes is paralleled by down-regulation of MHC-II, whereas brain-derived mononuclear cells neither ramified nor up-regulated MHC-II in OSSCs. Thus, brain-derived mononuclear cells maintain their MHC-II-negative phenotype within the environment of an immune organ. Intraparenchymal CD11c-positive cells share immunophenotypical characteristics of DCs from other organs but remain unique for their low MHC-II expression. GLIA 2014. © 2014 Wiley Periodicals, Inc.
    Glia 04/2015; 63(4). DOI:10.1002/glia.22771 · 6.03 Impact Factor
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    • "For example, even though they do not physically cross the blood–brain barrier, it is well established that both peripheral and central cytokine signaling potently influences behavior through receptors located on either side of endothelial cells (Dantzer et al., 2008; Capuron and Miller, 2011). Because the brain is highly sensitive to increases in proinflammatory cytokines , microglia tend to be highly regulated by anti-inflammatory ligands and receptors (e.g., CD200/CD200R (Lyons et al., 2007), CX 3 CR1/CX 3 CL1 (Cardona et al., 2006), or TGFb/TGFbR (Butovsky et al., 2014)). Although similar in morphology and phenotype to microglia, peripherally derived brain macrophages tend to be more inflammatory and less subject to immune regulation (Perry and Teeling, 2013).Along these same lines, RSD primes and activates peripherally derived monocytes inducing increased cytokine expression and resistance to the immunosuppressive effects of GCs (Engler et al., 2005; Wohleb et al., 2011, 2014a; Powell et al., 2013). "
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    ABSTRACT: The development and exacerbation of depression and anxiety are associated with exposure to repeated psychosocial stress. Stress is known to affect the bidirectional communication between the nervous and immune systems leading to elevated levels of stress mediators including glucocorticoids (GCs) and catecholamines and increased trafficking of proinflammatory immune cells. Animal models, like the repeated social defeat (RSD) paradigm, were developed to explore this connection between stress and affective disorders. RSD induces activation of the sympathetic nervous system (SNS) and hypothalamic-pituitary (HPA) axis activation, increases bone marrow production and egress of primed, GC-insensitive monocytes, and stimulates the trafficking of these cells to tissues including the spleen, lung, and brain. Recently, the observation that these monocytes have the ability to traffic to the brain perivascular spaces and parenchyma have provided mechanisms by which these peripheral cells may contribute to the prolonged anxiety-like behavior associated with RSD. The data that have been amassed from the RSD paradigm and others recapitulate many of the behavioral and immunological phenotypes associated with human anxiety disorders and may serve to elucidate potential avenues of treatment for these disorders. Here, we will discuss novel and key data that will present an overview of the neuroendocrine, immunological and behavioral responses to social stressors. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.
    Neuroscience 01/2015; 289. DOI:10.1016/j.neuroscience.2015.01.001 · 3.36 Impact Factor
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