Effects of cytokines on microglial phenotypes and astroglial coupling in an inflammatory coculture model

Hinkerohe, Daniel; Smikalla, Dirk; Haghikia, Aiden; Heupel, Katharina; Haase, Claus G.; Dermietzel, Rolf; Faustmann, Pedro M.

doi:10.1002/glia.20223

Cited by 75 publications

(87 citation statements)

References 72 publications

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“…As CXCL12 is expressed in high levels in the normal CNS, it is more logical that it would exert anti-inflammatory effects under normal circumstances. Consistent with this possibility, we found that AMD3100-treated mice had significantly increased levels of IFN-␥, decreased levels of IL-10, and increased levels of cytokines and chemokines associated with monocyte and microglial activation, including TNF-␣ and CXCL10 (72,73), indicating that CXCR4 activation is antiinflammatory in the spinal cord. Others have reported that CXCR4 expression by cells of myeloid lineage is dynamic and regulated by the activation state of the cell (74,75).…”

Section: Discussionsupporting

confidence: 74%

CXCL12 Limits Inflammation by Localizing Mononuclear Infiltrates to the Perivascular Space during Experimental Autoimmune Encephalomyelitis

McCandless¹,

Wang

Woerner

et al. 2006

The Journal of Immunology

229

262

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The inflammatory response in the CNS begins with the movement of leukocytes across the blood-brain barrier in a multistep process that requires cells to pass through a perivascular space before entering the parenchyma. The molecular mechanisms that orchestrate this movement are not known. The chemokine CXCL12 is highly expressed throughout the CNS by microendothelial cells under normal conditions, suggesting it might play a role maintaining the blood-brain barrier. We tested this hypothesis in the setting of experimental autoimmune encephalomyelitis (EAE) by using AMD3100, a specific antagonist of the CXCL12 receptor CXCR4. We demonstrate that the loss of CXCR4 activation enhances the migration of infiltrating leukocytes into the CNS parenchyma. CXCL12 is expressed at the basolateral surface of CNS endothelial cells in normal spinal cord and at the onset of EAE. This polarity is lost in vessels associated with an extensive parenchymal invasion of mononuclear cells during the peak of disease. Inhibition of CXCR4 activation during the induction of EAE leads to loss of the typical intense perivascular cuffs, which are replaced with widespread white matter infiltration of mononuclear cells, worsening the clinical severity of the disease and increasing inflammation. Taken together, these data suggest a novel anti-inflammatory role for CXCL12 during EAE in that it functions to localize CXCR4-expressing mononuclear cells to the perivascular space, thereby limiting the parenchymal infiltration of autoreactive effector cells.

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Section: Discussionsupporting

confidence: 74%

CXCL12 Limits Inflammation by Localizing Mononuclear Infiltrates to the Perivascular Space during Experimental Autoimmune Encephalomyelitis

McCandless¹,

Wang

Woerner

et al. 2006

The Journal of Immunology

229

262

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“…This contrasts with previous findings that Cx26 and Cx43 expression down-regulated MCP-1 levels in glioblastoma cells, leading to suppressed growth (41), and may suggest some cell type differences. Similarly, there have been many reports positively correlating expression levels of IL-6 and connexins as a part of the inflammatory response (42)(43)(44)(45); however, these all propose IL-6-mediated up-regulation of connexins rather than the connexin-mediated regulation of IL-6 as seen in this study. Our results indicate that not all proangiogenic or antiangiogenic molecules are regulated in synergy, which highlights the complexity of connexin-mediated pathways that likely are involved in cell growth and differentiation under various stimuli and in distinct cell types.…”

Section: Discussionmentioning

confidence: 41%

Connexins Act as Tumor Suppressors in Three-dimensional Mammary Cell Organoids by Regulating Differentiation and Angiogenesis

McLachlan¹,

Shao²,

Wang³

et al. 2006

Cancer Research

198

175

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Connexins are tumor suppressors, and human breast connexin 26 (Cx26) and connexin 43 (Cx43) gap junctions are often down-regulated in breast cancer. We previously showed that Cx26 and Cx43 overexpressed in MDA-MB-231 breast cancer cells inhibited tumor growth in vivo but not in twodimensional cultures. In the current study, we show that overexpression of Cx26 or Cx43 has tumor-suppressive properties in a three-dimensional environment such that they reduced anchorage-independent cell growth and induced partial redifferentiation of three-dimensional organoids of MDA-MB-231 cells. Importantly, the majority of exogenous connexins did not localize to the cell-cell interface or rescue gap junctional intercellular communication (GJIC) as assessed by dye transfer, providing evidence of a GJIC-independent mechanism of mammary tumor suppression. To further elucidate the mechanisms involved in connexin-induced three-dimensional redifferentiation of tumor cells, we examined whether connexin expression has a role in epithelial to mesenchymal transition (EMT). Cx26 and Cx43 reduced cell migration, increased cytokeratin 18 expression, and decreased vimentin levels, indicating a shift from a mesenchymal towards an epithelial phenotype. In addition, we examined the role of connexins in angiogenesis by probing an angiogenesis antibody array with conditioned media from three-dimensional MDA-MB-231 cultures. This revealed that connexin overexpression regulated various angiogenesislinked proteins. Furthermore, secreted factors from connexin overexpressing cells inhibited endothelial cell tubulogenesis and migration, and xenografts of Cx43 overexpressing MDA-MB-231 cells showed reduced tumor angiogenesis. In summary, Cx26 and Cx43 inhibit the malignant properties of MDA-MB-231 cells via GJIC-independent mechanisms, including regulation of EMT and angiogenesis. (Cancer Res 2006; 66(20): 9886-94)

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“…2). We reasoned that because TNF is a potent activator of microglia (Aggarwal et al, 2000;Hinkerohe et al, 2005) and a known mediator of LPS action in peripheral tissues (Beutler, 2005), chronic infusion of DN-TNFs to block solTNF signaling during an inflammatory stimulus might prevent TH-positive cell loss in the SNpc of LPS-infused rats. Unbiased stereological measurements of TH-IR/NeuN neuron soma and fluorescence densitometry of TH-positive fiber density revealed that coinfusion of XENP345 (70 ng/h) with LPS (5 ng/h) for 14 d into rat substantia nigra rescued ϳ50% of the LPS-induced nigrostriatal degeneration measured 8 weeks after the start of infusion (Fig.…”

Section: Resultsmentioning

confidence: 99%

Blocking Soluble Tumor Necrosis Factor Signaling with Dominant-Negative Tumor Necrosis Factor Inhibitor Attenuates Loss of Dopaminergic Neurons in Models of Parkinson's Disease

McCoy¹,

Martinez²,

Ruhn³

et al. 2006

J. Neurosci.

338

276

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The mechanisms that trigger or contribute to loss of dopaminergic (DA) neurons in Parkinson's disease (PD) remain unclear and controversial. Elevated levels of tumor necrosis factor (TNF) in CSF and postmortem brains of PD patients and animal models of PD implicate this proinflammatory cytokine in the pathophysiology of the disease; but a role for TNF in mediating loss of DA neurons in PD has not been clearly demonstrated. Here, we report that neutralization of soluble TNF (solTNF) in vivo with the engineered dominantnegative TNF compound XENP345 (a PEGylated version of the TNF variant A145R/I97T) reduced by 50% the retrograde nigral degeneration induced by a striatal injection of the oxidative neurotoxin 6-hydroxydopamine (6-OHDA). XENP345 was neuroprotective only when infused into the nigra, not the striatum. XENP345/6-OHDA rats displayed attenuated amphetamine-induced rotational behavior, indicating preservation of striatal dopamine levels. Similar protective effects were observed with chronic in vivo coinfusion of XENP345 with bacterial lipopolysaccharide (LPS) into the substantia nigra, confirming a role for solTNF-dependent neuroinflammation in nigral degeneration. In embryonic rat midbrain neuron/glia cell cultures exposed to LPS, even delayed administration of XENP345 prevented selective degeneration of DA neurons despite sustained microglia activation and secretion of solTNF. XENP345 also attenuated 6-OHDAinduced DA neuron toxicity in vitro. Collectively, our data demonstrate a role for TNF in vitro and in vivo in two models of PD, and raise the possibility that delaying the progressive degeneration of the nigrostriatal pathway in humans is therapeutically feasible with agents capable of blocking solTNF in early stages of PD.

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Effects of cytokines on microglial phenotypes and astroglial coupling in an inflammatory coculture model

Cited by 75 publications

References 72 publications

CXCL12 Limits Inflammation by Localizing Mononuclear Infiltrates to the Perivascular Space during Experimental Autoimmune Encephalomyelitis

CXCL12 Limits Inflammation by Localizing Mononuclear Infiltrates to the Perivascular Space during Experimental Autoimmune Encephalomyelitis

Connexins Act as Tumor Suppressors in Three-dimensional Mammary Cell Organoids by Regulating Differentiation and Angiogenesis

Blocking Soluble Tumor Necrosis Factor Signaling with Dominant-Negative Tumor Necrosis Factor Inhibitor Attenuates Loss of Dopaminergic Neurons in Models of Parkinson's Disease

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