Selective expression and cellular localization of pro-inflammatory chemokine ligand/receptor pairs in the sciatic nerves of a severe murine experimental autoimmune neuritis model of Guillain-Barré syndrome

Xia, Robin H.; Yosef, Nejla; Ubogu, Eroboghene E.

doi:10.1111/j.1365-2990.2010.01092.x

Cited by 37 publications

(70 citation statements)

References 25 publications

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“…We recently characterized a severe murine EAN that recapitulates the clinical, electrophysiological and pathologic features of severe demyelinating forms of GBS [31]. We have demonstrated increased expression of chemokines CCL2, CCL5 and CXCL10 and receptors CCR1, CCR2, CCR5 and CXCR3 in the sciatic nerves of affected mice relative to controls [32]. In this murine model, CCL2 localized to Schwann cells, CCL5 to axons and CXCL10 to endoneurial endothelial cells, with expression of CXCR3 on infiltrating T-cells and CCR2, CCR1 and CCR5 on both endoneurial macrophages and infiltrating T-cells [32].…”

Section: Autoimmune Neuropathiesmentioning

confidence: 93%

“…We have demonstrated increased expression of chemokines CCL2, CCL5 and CXCL10 and receptors CCR1, CCR2, CCR5 and CXCR3 in the sciatic nerves of affected mice relative to controls [32]. In this murine model, CCL2 localized to Schwann cells, CCL5 to axons and CXCL10 to endoneurial endothelial cells, with expression of CXCR3 on infiltrating T-cells and CCR2, CCR1 and CCR5 on both endoneurial macrophages and infiltrating T-cells [32]. These observations are highly suggestive that these chemokine ligand-receptor pairs are pathologically relevant in AIN.…”

Section: Autoimmune Neuropathiesmentioning

confidence: 95%

“…The question remains whether isolated blockade of T-cell infiltration in AIN will sufficiently treat these disorders. Observational data supporting endothelial expression of CXCL10 in association with increased T-cell trafficking in GBS and CIDP [25], as well as in the severe murine EAN model [32] compared to controls suggests that CXCL10-CXCR3 signaling may be crucial for pathogenic T-cell migration in GBS and CIDP. CXCR3 binds to CXCL9 and CXCL11, two other chemokines induced by interferon-during inflammatory processes [66], so CXCR3 blockade would be preferable to antagonists directed against CXCL10 alone.…”

Section: Where Do We Start In Peripheral Nerve Inflammation and Neuromentioning

confidence: 96%

“…Our recent development of an in vitro model of the human blood-nerve barrier [60] and advancements in murine AIN models (e.g. severe murine-EAN in Swiss Jim Lambert mice and spontaneous autoimmune peripheral polyneuropathy in CD86 deficient non-obese diabetic mice, a model of CIDP) [31,32,61], as well as advancements by others using rodent models of neuropathic pain should aid in deducing the roles of specific chemokine ligand-receptors pairs in these disorders. Such work will provide the necessary proof-of principle pre-requisite needed to initiate early phase clinical trials of chemokine receptor antagonists in GBS/CIDP and neuropathic pain.…”

Section: Chemokine Receptor Antagonists In Human Disordersmentioning

confidence: 99%

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Chemokine Receptors as Specific Anti-Inflammatory Targets in Peripheral Nerves

Ubogu

2011

EMIDDT

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Chemokines are the initial mediators of leukocyte migration across concentration gradients in vitro and to sites of inflammation in vivo. Chemokines signal via specific seven-transmembrane spanning G-protein coupled receptors (GPCRs). About 50 chemokine ligands and 18 receptors have been identified to date, and several are involved in leukocyte trafficking in human inflammation. Several chemokines signal via a single receptor, while others signal via multiple receptors. This redundancy may be necessary to mediate essential biological processes in vivo. There is evidence that specific chemokines and their receptors are expressed in the peripheral nerves or cerebrospinal fluid of patients with autoimmune neuropathies such as Guillain-Barré syndrome and Chronic Inflammatory Demyelinating Polyradiculoneuropathy and their animal models. Hematogenous leukocyte trafficking and chemokine-mediated signaling has also been implicated in the generation of neuropathic pain following peripheral nerve injury. Chemokine receptors, being GPCRs, provide an attractive drug target for modulating the harmful effects of peripheral nerve inflammation. The efficacy of anti-inflammatory therapies, including treatments that restrict leukocyte migration, has been established in several inflammatory disorders such as multiple sclerosis. There are several ongoing clinical trials testing chemokine receptor antagonists as specific anti-inflammatory drugs. This review evaluates the current status of the chemokine biology of peripheral neuropathies, highlighting areas where further studies are needed and discusses potentially selective drug targets for peripheral nerve inflammation and neuropathic pain.

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Section: Autoimmune Neuropathiesmentioning

confidence: 93%

Section: Autoimmune Neuropathiesmentioning

confidence: 95%

Section: Where Do We Start In Peripheral Nerve Inflammation and Neuromentioning

confidence: 96%

Section: Chemokine Receptor Antagonists In Human Disordersmentioning

confidence: 99%

See 2 more Smart Citations

Chemokine Receptors as Specific Anti-Inflammatory Targets in Peripheral Nerves

Ubogu

2011

EMIDDT

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“…Supported by observational studies showing increased CCR2 positive mononuclear cells in AIDP nerve biopsies and increased CCL2 and CCR2 in EAN mice sciatic nerves [22,101,148,66], CCL2-CCR2-mediated leukocyte trafficking is proposed to drive pathogenic monocyte and a subset of T lymphocyte trafficking across the BNB.…”

Section: Introductionmentioning

confidence: 99%

Inflammatory neuropathies: pathology, molecular markers and targets for specific therapeutic intervention

Ubogu

2015

Acta Neuropathol

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Inflammatory neuropathies encompass groups of heterogeneous disorders characterized by pathogenic immune-mediated hematogenous leukocyte infiltration of peripheral nerves, nerve roots or both, with resultant demyelination or axonal degeneration or both. Inflammatory neuropathies may be divided into three major disease categories: Guillain-Barré syndrome (particularly the acute inflammatory demyelinating polyradiculoneuropathy variant), Chronic inflammatory demyelinating polyradiculoneuropathy and nonsystemic vasculitic neuropathy (or peripheral nerve vasculitis). Despite major advances in molecular biology, pathology and genetics, the pathogenesis of these disorders remains elusive. There is insufficient knowledge on the mechanisms of hematogenous leukocyte trafficking into the peripheral nervous system to guide the development of specific molecular therapies for immune-mediated inflammatory neuropathies compared to disorders such as psoriasis, inflammatory bowel disease, rheumatoid arthritis or multiple sclerosis. The recent isolation and characterization of human endoneurial endothelial cells that form the blood-nerve barrier provides an opportunity to elucidate leukocyte-endothelial cell interactions critical to the pathogenesis of inflammatory neuropathies at the interface between the systemic circulation and peripheral nerve endoneurium. This review discusses our current knowledge of the classic pathological features of inflammatory neuropathies, attempts at molecular classification and genetic determinants, the utilization of in vitro and in vivo animal models to determine pathogenic mechanisms at the interface between the systemic circulation and the peripheral nervous system relevant to these disorders and prospects for future potential molecular pathology biomarkers and targets for specific therapeutic intervention.

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Dynamic impact of brief electrical nerve stimulation on the neural immune axis—polarization of macrophages toward a pro‐repair phenotype in demyelinated peripheral nerve

McLean

Verge

2016

Glia

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Demyelinating peripheral nerves are infiltrated by cells of the monocyte lineage, including macrophages, which are highly plastic, existing on a continuum from pro-inflammatory M1 to pro-repair M2 phenotypic states. Whether one can therapeutically manipulate demyelinated peripheral nerves to promote a pro-repair M2 phenotype remains to be elucidated. We previously identified brief electrical nerve stimulation (ES) as therapeutically beneficial for remyelination, benefits which include accelerated clearance of macrophages, making us theorize that ES alters the local immune response. Thus, the impact of ES on the immune microenvironment in the zone of demyelination was examined. Adult male rat tibial nerves were focally demyelinated via 1% lysophosphatidyl choline (LPC) injection. Five days later, half underwent 1 hour 20 Hz sciatic nerve ES proximal to the LPC injection site. ES had a remarkable and significant impact, shifting the macrophage phenotype from predominantly pro-inflammatory/M1 toward a predominantly pro-repair/M2 one, as evidenced by an increased incidence of expression of M2-associated phenotypic markers in identified macrophages and a decrease in M1-associated marker expression. This was discernible at 3 days post-ES (8 days post-LPC) and continued at the 5 day post-ES (10 days post-LPC) time point examined. ES also affected chemokine (C-C motif) ligand 2 (CCL2; aka MCP-1) expression in a manner that correlated with increases and decreases in macrophage numbers observed in the demyelination zone. The data establish that briefly increasing neuronal activity favorably alters the immune microenvironment in demyelinated nerve, rapidly polarizing macrophages toward a pro-repair phenotype, a beneficial therapeutic concept that may extend to other pathologies. GLIA 2016;64:1546-1561.

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Selective expression and cellular localization of pro-inflammatory chemokine ligand/receptor pairs in the sciatic nerves of a severe murine experimental autoimmune neuritis model of Guillain-Barré syndrome

Cited by 37 publications

References 25 publications

Chemokine Receptors as Specific Anti-Inflammatory Targets in Peripheral Nerves

Chemokine Receptors as Specific Anti-Inflammatory Targets in Peripheral Nerves

Inflammatory neuropathies: pathology, molecular markers and targets for specific therapeutic intervention

Dynamic impact of brief electrical nerve stimulation on the neural immune axis—polarization of macrophages toward a pro‐repair phenotype in demyelinated peripheral nerve

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