Cutting Edge: Activity of Human Adult Microglia in Response to CC Chemokine Ligand 21

Dijkstra, Ineke M.; Hulshof, S. C. J.; Valk, Paul van der; Boddeke, Hendrikus; Biber, Knut

doi:10.4049/jimmunol.172.5.2744

Cited by 48 publications

(46 citation statements)

References 27 publications

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“…Furthermore, we were able to show that CCL21 activates microglia via the chemokine receptor CXCR3 (Biber et al, 2001(Biber et al, , 2002Rappert et al, 2002;Dijkstra et al, 2004). Subsequent studies showed that mice deficient for CXCR3 displayed no secondary activation of microglia in response to enthorinal cortex lesion.…”

Section: Introductionmentioning

confidence: 83%

“…The expression plasmid for mCXCR3 (pcDNA3.1-mCXCR3) was described recently (Dijkstra et al, 2004), and the expression plasmid for mCCR7 (pRC/CMV-mCCR7) was a kind gift from Dr. U. Hoekpen and Dr. M. Lipp (Max-Delbrück-Centrumfür Molekulare Medizin, Berlin, Germany). Mock transfections were performed with empty pEGFP-N2 vector.…”

Section: Transfection Of Cells Ng108 and Hek293 Cellsmentioning

confidence: 99%

“…Cell migration in response to neuronal supernatants or chemokines was assessed using a 48-well chemotaxis microchamber (Neuro Probe, Gaithersburg, MD) as described previously (Dijkstra et al, 2004). Chemokine stock solutions were prepared in PBS and further diluted in neuronal medium for use in the assay.…”

Section: Chemotaxis Assaymentioning

confidence: 99%

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Vesicle-Mediated Transport and Release of CCL21 in Endangered Neurons: A Possible Explanation for Microglia Activation Remote from a Primary Lesion

Jong¹,

Dijkstra²,

Hensens³

et al. 2005

J. Neurosci.

126

117

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Whenever neurons in the CNS are injured, microglia become activated. In addition to local activation, microglia remote from the primary lesion site are stimulated. Because this so-called secondary activation of microglia is instrumental for long-term changes after neuronal injury, it is important to understand how microglia activity is controlled. The remote activation of microglia implies that the activating signals are transported along neuronal projections. However, the identity of these signals has not yet been identified. It is shown here that glutamate-treated neurons rapidly express and release the chemokine CCL21. We also provide evidence that neuronal CCL21 is packed in vesicles and transported throughout neuronal processes to reach presynaptic structures. Chemotaxis assays show that functional CCL21 is released from endangered neurons and activate microglia via the chemokine receptor CXCR3. Based on these findings, we suggest that neuronal CCL21 is important in directed neuron-microglia signaling and that this communication could account for the remote activation of microglia, far distant from a primary lesion.

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Section: Introductionmentioning

confidence: 83%

Section: Transfection Of Cells Ng108 and Hek293 Cellsmentioning

confidence: 99%

See 1 more Smart Citation

Vesicle-Mediated Transport and Release of CCL21 in Endangered Neurons: A Possible Explanation for Microglia Activation Remote from a Primary Lesion

Jong¹,

Dijkstra²,

Hensens³

et al. 2005

J. Neurosci.

126

117

View full text Add to dashboard Cite

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“…Microglia activated by LPS stimulation in vitro (Dijkstra et al, 2006), in multiple sclerosis lesions (Serafini et al, 2006), and in models of experimental autoimmune encephalomyelitis during symptom onset and progression (Columba-Cabezas et al, 2003;Dijkstra et al, 2006), have been shown to upregulate the CCR7 receptor. Microglia also respond to CCL21 via lower-affinity activation of the CXCR3 receptor (Murphy et al, 2000;Biber et al, 2001;Rappert et al, 2002;Dijkstra et al, 2004). CXCR3 is also expressed by astrocytes and neurons; however, CCL21 is not a functional ligand for CXCR3 in these cells de Jong et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Modulation of Thalamic Nociceptive Processing after Spinal Cord Injury through Remote Activation of Thalamic Microglia by Cysteine–Cysteine Chemokine Ligand 21

Zhao¹,

Waxman²,

Hains³

2007

J. Neurosci.

203

143

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Spinal cord injury (SCI) results in the generation and amplification of pain caused in part by injury-induced changes in neuronal excitability at multiple levels along the sensory neuraxis. We have previously shown that activated microglia, through an ERK (extracellular signal-regulated kinase)-regulated PGE 2 (prostaglandin E 2 ) signaling mechanism, maintain neuronal hyperexcitability in the lumbar dorsal horn. Here, we examined whether microglial cells in the thalamus contribute to the modulation of chronic pain after SCI, and whether microglial activation is governed by spinally mediated increases in the microglial activator cysteine-cysteine chemokine ligand 21 (CCL21). We report that CCL21 is upregulated in dorsal horn neurons, that tissue levels are increased in the dorsal horn and ventral posterolateral (VPL) nucleus of the thalamus 4 weeks after SCI, and that the increase can be differentially reduced by spinal blockade at T1 or L1. In intact animals, electrical stimulation of the spinothalamic tract induces increases in thalamic CCL21 levels. Recombinant CCL21 injected into the VPL of intact animals transiently activates microglia and induces pain-related behaviors, effects that could be blocked with minocycline. After SCI, intra-VPL antibody-mediated neutralization of CCL21 decreases microglial activation and evoked hyperexcitability of VPL neurons, and restores nociceptive thresholds to near-normal levels. These data identify a novel pathway by which SCI triggers upregulation of the neuroimmune modulator CCL21 in the thalamus, which induces microglial activation in association with pain phenomena.

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“…Also in some human cells, CCL21 is a functional ligand for endogenously expressed CXCR3 (Dijkstra et al, 2004;Poggi et al, 2004). To investigate whether CXCR3 can transduce the ligand signals in colon cancer cells, we first performed calcium mobilization assays.…”

Section: Expression Of Chemokine Receptors Cxcr3 Cxcr4 and Ccr7 In Cmentioning

confidence: 99%

Chemokine receptor CXCR3 promotes colon cancer metastasis to lymph nodes

et al. 2007

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Chemokines and their receptors are essential for leukocyte trafficking, and also implicated in cancer metastasis to specific organs. We have recently demonstrated that CXCR3 plays a critical role in metastasis of mouse melanoma cells to lymph nodes. Here, we show that some human colon cancer cell lines express CXCR3 constitutively. We constructed cells that expressed CXCR3 cDNA ('DLD-1-CXCR3'), and compared with nonexpressing controls by rectal transplantation in nude mice. Although both cell lines disseminated to lymph nodes at similar frequencies at 2 weeks, DLD-1-CXCR3 expanded more rapidly than the control in 4 weeks. In 6 weeks, 59% of mice inoculated with DLD1-CXCR3 showed macroscopic metastasis in para-aortic lymph nodes, whereas only 14% of those with the control (Po0.05). In contrast, metastasis to the liver or lung was rare, and unaffected by CXCR3 expression. In clinical colon cancer samples, we found expression of CXCR3 in 34% cases, most of which had lymph node metastasis. Importantly, patients with CXCR3-positive cancer showed significantly poorer prognosis than those without CXCR3, or those expressing CXCR4 or CCR7. These results indicate that activation of CXCR3 with its ligands stimulates colon cancer metastasis preferentially to the draining lymph nodes with poorer prognosis.

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Cutting Edge: Activity of Human Adult Microglia in Response to CC Chemokine Ligand 21

Cited by 48 publications

References 27 publications

Vesicle-Mediated Transport and Release of CCL21 in Endangered Neurons: A Possible Explanation for Microglia Activation Remote from a Primary Lesion

Vesicle-Mediated Transport and Release of CCL21 in Endangered Neurons: A Possible Explanation for Microglia Activation Remote from a Primary Lesion

Modulation of Thalamic Nociceptive Processing after Spinal Cord Injury through Remote Activation of Thalamic Microglia by Cysteine–Cysteine Chemokine Ligand 21

Chemokine receptor CXCR3 promotes colon cancer metastasis to lymph nodes

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