Regulation of chemokine receptor expression in human microglia and astrocytes

Flynn, Geraldine; Maru, Seema; Loughlin, Jane; Romero, Ignacio A.; Male, David

doi:10.1016/s0165-5728(03)00009-2

Cited by 192 publications

(146 citation statements)

References 36 publications

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“…It has been shown previously that microglia are able to produce CXCL10 and express its receptor CXCR3 25. Our observation of CXCL10 production by antigen‐specific T cells uncovers a new, potentially clinically relevant dimension to T cell inflammation in the brain.…”

Section: Discussionsupporting

confidence: 55%

A destructive feedback loop mediated by CXCL10 in central nervous system inflammatory disease

Roberts

Blachère

Frank

et al. 2015

Annals of Neurology

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ObjectiveParaneoplastic neurologic disorders (PND) are autoimmune diseases associated with cancer and ectopic expression of a neuronal antigen in a peripheral tumor. Patients with PND harbor high‐titer antibodies and T cells in their serum and cerebrospinal fluid (CSF) that are specific to the tumor antigen, and treatment with the immunosuppressant FK506 (tacrolimus) decreases CSF white blood cell counts. The objective of this study was to determine the effect of FK506 on CSF chemokine levels in PND patients.MethodsCSF samples before and after FK506 treatment were tested by multiplex assay for the presence of 27 cytokines. Follow‐up in vitro experiments aimed to determine whether T cells secrete CXCL10 in response to cognate antigen.ResultsHere we report that PND patients harbor high levels of the chemokine CXCL10 in their CSF. CXCL10 is a cytokine that recruits CXCR3+ cells such as activated T cells, and we found that FK506 treatment specifically decreased CSF CXCL10 from among 27 cytokines tested. In vitro, CXCL10 was only produced during antigen‐specific cognate interactions between T cells and antigen‐presenting cells (APCs) when interferon‐γ (IFNγ) receptors were present on the T cell.InterpretationThese results support a model in which antigen‐specific T cell stimulation by PND APCs triggers IFNγ, followed by CXCL10 production and further lymphocyte recruitment, suggesting that treatments targeting T cells or CXCL10 in the central nervous system (CNS) may interrupt a destructive positive feedback loop present in CNS inflammation. Ann Neurol 2015;78:619–629

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Section: Discussionsupporting

confidence: 55%

A destructive feedback loop mediated by CXCL10 in central nervous system inflammatory disease

Roberts

Blachère

Frank

et al. 2015

Annals of Neurology

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“…CXCL12/ SDF-1 gene expression was not significantly affected (Table 1). A recent study of the adult human microglial cell line CHME3 found no significant modulation of chemokine receptor expression after exposure to IFN-g, including CXCR4, although in the murine system, CXCR4 has been shown to be suppressed by IFN-g. 30,31 The suppression of the CXCR4 gene in human fetal microglial cells as found in the current investigation may represent a unique response of fetal microglia as compared with adult microglia. Further studies will be required to investigate this hypothesis.…”

Section: Ifn-c-regulated Genes Of Human Microglia Rb Rock Et Almentioning

confidence: 68%

Transcriptional response of human microglial cells to interferon-γ

Rock

Deshpande

et al. 2005

Genes Immun

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Microglia, the resident macrophages in the central nervous system (CNS), play a pivotal role in innate and adaptive immune responses in the brain. The immune functions of microglia are regulated by cytokines, including interferon (IFN)-g, which is a major mediator of macrophage activation. We describe the transcriptional profile of human fetal microglial cells at 1, 6, and 24 h after IFN-g treatment. The results show a change in the expression of 405 genes including transcriptionally induced chemokines, IFN-g signaling factors, and major histocompatibility complex genes. Our results demonstrate that activation of microglia by IFN-g induces proinflammatory T-lymphocyte-related chemokine genes as well as genes involved in antigen presentation. As a result, signals for T-cell infiltration and antigen presentation are produced to allow for microglia-T-cell interactions that likely contribute to defense against invading pathogens. In sum, our results provide a foundation for the molecular mechanisms of the microglial response to IFN-g-a key to understanding cell-mediated immunity of the CNS.

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“…The CXCL10/CXCR3 axis plays a critical role in inflammation by recruiting activated T lymphocytes, monocytes, and macrophages. 12,14,58,60 We found that CXCL10 expression is up-regulated in cells, including RGCs, after axonal injury, which is associated with leukocyte recruitment and infiltration in neural retina. To investigate potential mechanisms of CXCR3-mediated RGC death in TON, we deleted CXCR3 in leukocytes and found that leukocyte recruitment is attenuated and RGC survival is increased.…”

Section: Discussionmentioning

confidence: 80%

Critical Role of the CXCL10/C-X-C Chemokine Receptor 3 Axis in Promoting Leukocyte Recruitment and Neuronal Injury during Traumatic Optic Neuropathy Induced by Optic Nerve Crush

Liu

Zhu

et al. 2017

The American Journal of Pathology

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Traumatic optic neuropathy (TON) is an acute injury of the optic nerve secondary to trauma. Loss of retinal ganglion cells (RGCs) is a key pathological process in TON, yet mechanisms responsible for RGC death remain unclear. In a mouse model of TON, real-time noninvasive imaging revealed a dramatic increase in leukocyte rolling and adhesion in veins near the optic nerve (ON) head at 9 hours after ON injury. Although RGC dysfunction and loss were not detected at 24 hours after injury, massive leukocyte infiltration was observed in the superficial retina. These cells were identified as T cells, microglia/monocytes, and neutrophils but not B cells. CXCL10 is a chemokine that recruits leukocytes after binding to its receptor C-X-C chemokine receptor (CXCR) 3. The levels of CXCL10 and CXCR3 were markedly elevated in TON, and up-regulation of CXCL10 was mediated by STAT1/3. Deleting CXCR3 in leukocytes significantly reduced leukocyte recruitment, and prevented RGC death at 7 days after ON injury. Treatment with CXCR3 antagonist attenuated TON-induced RGC dysfunction and cell loss. In vitro co-culture of primary RGCs with leukocytes resulted in increased RGC apoptosis, which was exaggerated in the presence of CXCL10. These results indicate that leukocyte recruitment in retinal vessels near the ON head is an early event in TON and the CXCL10/CXCR3 axis has a critical role in recruiting leukocytes and inducing RGC death. (Am J Pathol 2017, 187: 352e365; http://dx

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Regulation of chemokine receptor expression in human microglia and astrocytes

Cited by 192 publications

References 36 publications

A destructive feedback loop mediated by CXCL10 in central nervous system inflammatory disease

A destructive feedback loop mediated by CXCL10 in central nervous system inflammatory disease

Transcriptional response of human microglial cells to interferon-γ

Critical Role of the CXCL10/C-X-C Chemokine Receptor 3 Axis in Promoting Leukocyte Recruitment and Neuronal Injury during Traumatic Optic Neuropathy Induced by Optic Nerve Crush

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