CC Chemokine Receptors and Chronic Inflammation—Therapeutic Opportunities and Pharmacological Challenges

White, Gemma E.; Iqbal, Asif; Greaves, David R.

doi:10.1124/pr.111.005074

Cited by 247 publications

(213 citation statements)

References 424 publications

(406 reference statements)

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“…We evaluated whether VCR can activate endothelial cells and quantified expression of selected adhesion molecules. We focused on ICAM-1 (CD54) and VCAM-1 (CD106), which are 2 integrin-binding endothelial cell adhesion molecules that play a fundamental role in the processes of monocyte intravascular crawling, firm adhesion to postcapillary venules, and migration in the subendothelial space (27)(28)(29)(30). Incubation of primary HUVECs with VCR (10 nM) induced a significant increase of VCAM-1 + CD31 + cells ( Figure 5, A and B), as quantified at 18 hours by flow cytometry, with over a 3-fold increase over basal expression.…”

Section: Figurementioning

confidence: 99%

Monocytes expressing CX3CR1 orchestrate the development of vincristine-induced pain

Old

Nadkarni²,

Grist³

et al. 2014

J. Clin. Invest.

150

185

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A major dose-limiting side effect associated with cancer-treating antineoplastic drugs is the development of neuropathic pain, which is not readily relieved by available analgesics. A better understanding of the mechanisms that underlie pain generation has potential to provide targets for prophylactic management of chemotherapy pain. Here, we delineate a pathway for pain that is induced by the chemotherapeutic drug vincristine sulfate (VCR). In a murine model of chemotherapy-induced allodynia, VCR treatment induced upregulation of endothelial cell adhesion properties, resulting in the infiltration of circulating CX3CR1 + monocytes into the sciatic nerve. At the endothelial-nerve interface, CX3CR1 + monocytes were activated by the chemokine CX3CL1 (also known as fractalkine [FKN]), which promoted production of reactive oxygen species that in turn activated the receptor TRPA1 in sensory neurons and evoked the pain response. Furthermore, mice lacking CX3CR1 exhibited a delay in the development of allodynia following VCR administration. Together, our data suggest that CX3CR1 antagonists and inhibition of FKN proteolytic shedding, possibly by targeting ADAM10/17 and/or cathepsin S, have potential as peripheral approaches for the prophylactic treatment of chemotherapy-induced pain.

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Section: Figurementioning

confidence: 99%

Monocytes expressing CX3CR1 orchestrate the development of vincristine-induced pain

Old

Nadkarni²,

Grist³

et al. 2014

J. Clin. Invest.

150

185

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“…CCL2 belongs to a family of chemotactic cytokines (8 kDa), which bind to G protein-coupled receptors to regulate recruitment of macrophages during normal physiologic responses, such as wound healing. [27][28][29] CCL2 modulates macrophage recruitment to breast tumors and also signals to breast cancer cells to modulate tumor survival and invasion. [30][31][32][33] Antibody neutralization of CCL2 inhibits growth and invasion of breast tumor xenografts.…”

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confidence: 99%

Elevated expression of chemokine C-C ligand 2 in stroma is associated with recurrent basal-like breast cancers

Yao

Staggs

et al. 2016

Modern Pathology

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Despite advances in treatment, up to 30% of breast cancer patients experience disease recurrence accompanied by more aggressive disease and poorer prognosis. Treatment of breast cancer is complicated by the presence of multiple breast cancer subtypes, including: luminal, Her2 overexpressing, and aggressive basal-like breast cancers. Identifying new biomarkers specific to breast cancer subtypes could enhance the prediction of patient prognosis and contribute to improved treatment strategies. The microenvironment influences breast cancer progression through expression of growth factors, angiogenic factors and other soluble proteins. In particular, chemokine C-C ligand 2 (CCL2) regulates macrophage recruitment to primary tumors and signals to cancer cells to promote breast tumor progression. Here we employed a software-based approach to evaluate the prognostic significance of CCL2 protein expression in breast cancer subtypes in relation to its expression in the epithelium or stroma or in relation to fibroblast-specific protein 1 (Fsp1), a mesenchymal marker. Immunohistochemistry analysis of tissue microarrays revealed that CCL2 significantly correlated with Fsp1 expression in the stroma and tumor epithelium of invasive ductal carcinoma. In the overall cohort of invasive ductal carcinomas (n = 427), CCL2 and Fsp1 expression in whole tissues, stroma and epithelium were inversely associated with cancer stage and tumor size. When factoring in molecular subtype, stromal CCL2 was observed to be most highly expressed in basal-like breast cancers. By Cox regression modeling, stromal CCL2, but not epithelial CCL2, expression was significantly associated with decreased recurrence-free survival. Furthermore, stromal CCL2 (HR = 7.51 P = 0.007) was associated with a greater hazard than cancer stage (HR = 2.45, P = 0.048) in multivariate analysis. These studies indicate that stromal CCL2 is associated with decreased recurrence-free survival in patients with basal-like breast cancer, with important implications on the use of stromal markers for predicting patient prognosis.

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“…7 In the highly inflammatory setting of acute ischemic stroke, chemokines are generated by brain-resident microglial cells and infiltrating immune cells, resulting in further leukocyte attraction and activation. 8,9 Chemokines and their cognate receptors regulate both physiological and pathological processes in the central nervous system, and it is currently postulated that chemokines play a generally deleterious role by contributing to brain injury after cerebral ischemia-reperfusion. 10 We have shown that expression of numerous chemokinerelated genes is upregulated in the mouse brain from 4 hours for ≥3 days after ischemia-reperfusion, 11 raising the possibility that certain key chemokines/chemokine receptors could represent targets for acute stroke therapy.…”

mentioning

confidence: 99%

Effect of a Broad-Specificity Chemokine-Binding Protein on Brain Leukocyte Infiltration and Infarct Development

Lee

Chu

Kim

et al. 2015

Stroke

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Background and Purpose-Expression of numerous chemokine-related genes is increased in the brain after ischemicstroke. Here, we tested whether post-stroke administration of a chemokine-binding protein (CBP), derived from the parapoxvirus bovine papular stomatitis virus, might reduce infiltration of leukocytes into the brain and consequently limit infarct development. Methods-The binding spectrum of the CBP was evaluated in chemokine ELISAs, and binding affinity was determined using surface plasmon resonance. Focal stroke was induced in C57Bl/6 mice by middle cerebral artery occlusion for 1 hour followed by reperfusion for 23 or 47 hours. Mice were treated intravenously with either bovine serum albumin (10 μg) or CBP (10 μg) at the commencement of reperfusion. At 24 or 48 hours, we assessed plasma levels of the chemokines CCL2/MCP-1 and CXCL2/MIP-2, as well as neurological deficit, brain leukocyte infiltration, and infarct volume. Results-The CBP interacted with a broad spectrum of CC, CXC, and XC chemokines and bound CCL2/MCP-1 and CXCL2/MIP-2 with high affinity (pM range). Stroke markedly increased plasma levels of CCL2/MCP-1 and CXCL2/ MIP-2, as well as numbers of microglia and infiltrating leukocytes in the brain. Increases in plasma chemokines were blocked in mice treated with CBP, in which there was reduced neurological deficit, fewer brain-infiltrating leukocytes, and ≈50% smaller infarcts at 24 hours compared with bovine serum albumin-treated mice. However, CBP treatment was no longer protective at 48 hours. Conclusions-Post-stroke administration of CBP can reduce plasma chemokine levels in association with temporary attenuation of brain inflammation and infarct volume development.

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CC Chemokine Receptors and Chronic Inflammation—Therapeutic Opportunities and Pharmacological Challenges

Cited by 247 publications

References 424 publications

Monocytes expressing CX3CR1 orchestrate the development of vincristine-induced pain

Monocytes expressing CX3CR1 orchestrate the development of vincristine-induced pain

Elevated expression of chemokine C-C ligand 2 in stroma is associated with recurrent basal-like breast cancers

Effect of a Broad-Specificity Chemokine-Binding Protein on Brain Leukocyte Infiltration and Infarct Development

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