Systemic inflammation induces anxiety disorder through CXCL12/CXCR4 pathway

Yang, Le; Wang, M.; Guo, Yanyan; Sun, Ting; Li, Y.J.; Yang, Qi; Zhang, K.; Liu, S.B.; Zhao, Ming; Wu, Yumei

doi:10.1016/j.bbi.2016.03.001

Cited by 103 publications

(54 citation statements)

References 35 publications

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“…This process of immune-to-glutamate signaling ensures that EAAT uptake is not an all or none phenomenon, but a more nuanced, synapse-strengthening process. Recently, direct evidence implicating CXCL12/SDF1 in preclinical models of anxiety and other neuropsychiatric disorders have been published (Guyon, 2014;Yang et al, 2016). Astrocytes have recently been implicated to have a role in synaptic elimination during brain development in a manner similar to the role played by the microglia in developmental pruning (Chung et al, 2013).…”

Section: Synaptogenesis Gliotransmission and Circuit Integrationmentioning

confidence: 99%

Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders

Haroon

Miller

Sanacora

2016

Neuropsychopharmacol

412

299

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Increasing data indicate that inflammation and alterations in glutamate neurotransmission are two novel pathways to pathophysiology in mood disorders. The primary goal of this review is to illustrate how these two pathways may converge at the level of the glia to contribute to neuropsychiatric disease. We propose that a combination of failed clearance and exaggerated release of glutamate by glial cells during immune activation leads to glutamate increases and promotes aberrant extrasynaptic signaling through ionotropic and metabotropic glutamate receptors, ultimately resulting in synaptic dysfunction and loss. Furthermore, glutamate diffusion outside the synapse can lead to the loss of synaptic fidelity and specificity of neurotransmission, contributing to circuit dysfunction and behavioral pathology. This review examines the fundamental role of glia in the regulation of glutamate, followed by a description of the impact of inflammation on glial glutamate regulation at the cellular, molecular, and metabolic level. In addition, the role of these effects of inflammation on glia and glutamate in mood disorders will be discussed along with their translational implications.

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Section: Synaptogenesis Gliotransmission and Circuit Integrationmentioning

confidence: 99%

Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders

Haroon

Miller

Sanacora

2016

Neuropsychopharmacol

412

299

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“…Under pathological states, activated glial cells are the main source of SDF1. In LPS-induced systemic inflammation model and bone cancer pain model, SDF1 was predominantly released by activated astrocytes in the spinal cord (Shen et al, 2014; Hang et al, 2016; Yang L. et al, 2016). Microglia was also a main source of SDF1 production in the spinal cord of rats with spared nerve injury or ischemia-reperfusion injury (Bai et al, 2016; Li et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

SDF1-CXCR4 Signaling Maintains Central Post-Stroke Pain through Mediation of Glial-Neuronal Interactions

Yang

Luo

Sun

et al. 2017

Front. Mol. Neurosci.

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Central post-stroke pain (CPSP) is an intractable central neuropathic pain that has been poorly studied mechanistically. Here we showed that stromal cell-derived factor 1 (SDF1 or CXCL12), a member of the CXC chemokine family, and its receptor CXCR4 played a key role in the development and maintenance of thalamic hemorrhagic CPSP through hypoxia inducible factor 1α (HIF-1α) mediated microglial-astrocytic-neuronal interactions. First, both intra-thalamic collagenase (ITC) and SDF1 injections could induce CPSP that was blockable and reversible by intra-thalamic administration of both AMD3100 (a selective CXCR4 antagonist) and inhibitors of microglial or astrocytic activation. Second, long-term increased-expression of SDF1 and CXCR4 that was accompanied by activations of both microglia and astrocytes following ITC could be blocked by both AMD-3100 and YC-1, a selective inhibitor of HIF-1α. AMD-3100 could also inhibit release of proinflammatory mediators (TNFα, IL1β and IL-6). Increased-expression of HIF-1α, SDF1, CXCR4, Iba1 and GFAP proteins could be induced by both ITC and intra-thalamic CoCl2, an inducer of HIF-1α that was blockable by both HIF-1α inhibition and CXCR4 antagonism. Finally, inhibition of HIF-1α was only effective in prevention, but not in treatment of ITC-induced CPSP. Taken together, the present study demonstrated that in the initial process of thalamic hemorrhagic state HIF-1α up-regulated SDF1-CXCR4 signaling, while in the late process SDF1-CXCR4 signaling-mediated positive feedback plays more important role in glial-glial and glial-neuronal interactions and might be a novel promising molecular target for treatment of CPSP in clinic.

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“…However, available data about the CXCR4 receptor behavior are contradictory. Whereas some authors, using different models, have demonstrated that CXCR4 activation may promote reversion of cellular damage induced by several insults [6,11,34], other authors have reported the opposite [15,16,17]. In fact, the activation of CXCR4 chemokine receptor led to detrimental effects in these recent studies [14,15,16,17].…”

Section: Discussionmentioning

confidence: 99%

“…Conversely, other authors have demonstrated beneficial effects on neuronal function by blocking CXCR4 with AMD3100 [13,16,17]. …”

Section: Discussionmentioning

confidence: 99%

“…Upregulation of CXCR4 in the dorsal root ganglia and spinal cord contributes to the development and maintenance of neuropathic pain following nerve injury in rats [16]. Systemic inflammation induces anxiety disorder through the CXCR4/SDF-1α pathway [17]. These data show that CXCR4 receptor activation by SDF-1α may increase neuropathic pain, while CXCR4 receptor blockade in brain may have a protective effect on neurons.…”

Section: Introductionmentioning

confidence: 99%

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The Impact of CXCR4 Blockade on the Survival of Rat Brain Cortical Neurons

Merino

Garcimartín

López-Oliva

et al. 2016

IJMS

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Background: Chemokine receptor type 4 (CXCR4) plays a role in neuronal survival/cell repair and also contributes to the progression of cancer and neurodegenerative diseases. Chemokine ligand 12 (CXCL12) binds to CXCR4. In this study, we have investigated whether CXCR4 blockade by AMD3100 (a CXCR4 antagonist, member of bicyclam family) may affect neuronal survival in the absence of insult. Thus, we have measured the mitochondrial membrane potential (MMP), Bax and Bcl-2 protein translocation, and cytochrome c release in AMD3100-treated brain cortical neurons at 7 DIV (days in vitro). Methods: For this aim, AMD3100 (200 nM) was added to cortical neurons for 24 h, and several biomarkers like cell viability, reactive oxygen species (ROS) generation, lactate dehydrogenase (LDH) release, caspase-3/9 activity, proteins Bax and Bcl-2 translocation, and cytochrome c release were analyzed by immunoblot. Results: CXCR4 blockade by AMD3100 (200 nM, 24 h) induces mitochondrial hyperpolarization and increases caspase-3/9 hyperpolarization without affecting LDH release as compared to untreated controls. AMD3100 also increases cytochrome c release and promotes Bax translocation to the mitochondria, whereas it raises cytosolic Bcl-2 levels in brain cortical neurons. Conclusion: CXCR4 blockade induces cellular death via intrinsic apoptosis in rat brain cortical neurons in absence of insult.

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Systemic inflammation induces anxiety disorder through CXCL12/CXCR4 pathway

Cited by 103 publications

References 35 publications

Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders

Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders

SDF1-CXCR4 Signaling Maintains Central Post-Stroke Pain through Mediation of Glial-Neuronal Interactions

The Impact of CXCR4 Blockade on the Survival of Rat Brain Cortical Neurons

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