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Chemokine CCL2 and its receptor CCR2 in the medullary dorsal horn are involved in trigeminal neuropathic pain
Zhi-Jun Zhang, Yu-Lin Dong, Ying Lu, Su Cao, Zhi-Qi Zhao, Yong-Jing Gao
Journal of Neuroinflammation , 2012, DOI: 10.1186/1742-2094-9-136
Abstract: The inferior alveolar nerve and mental nerve transection (IAMNT) was used to induce trigeminal neuropathic pain. The expression of ATF3, CCL2, glial fibrillary acidic protein (GFAP), and CCR2 were detected by immunofluorescence histochemical staining and western blot. The cellular localization of CCL2 and CCR2 were examined by immunofluorescence double staining. The effect of a selective CCR2 antagonist, RS504393 on pain hypersensitivity was checked by behavioral testing.IAMNT induced persistent (>21?days) heat hyperalgesia of the orofacial region and ATF3 expression in the mandibular division of the trigeminal ganglion. Meanwhile, CCL2 expression was increased in the medullary dorsal horn (MDH) from 3?days to 21?days after IAMNT. The induced CCL2 was colocalized with astroglial marker GFAP, but not with neuronal marker NeuN or microglial marker OX-42. Astrocytes activation was also found in the MDH and it started at 3?days, peaked at 10?days and maintained at 21?days after IAMNT. In addition, CCR2 was upregulated by IAMNT in the ipsilateral medulla and lasted for more than 21?days. CCR2 was mainly colocalized with NeuN and few cells were colocalized with GFAP. Finally, intracisternal injection of CCR2 antagonist, RS504393 (1, 10?μg) significantly attenuated IAMNT-induced heat hyperalgesia.The data suggest that CCL2-CCR2 signaling may be involved in the maintenance of orofacial neuropathic pain via astroglial–neuronal interaction. Targeting CCL2-CCR2 signaling may be a potentially important new treatment strategy for trigeminal neuralgia.Neuropathic pain resulting from many types of injury to the nervous system is a devastating disease. The mechanisms by which nerve injury develops neuropathic pain have remained largely unknown. It was generally believed that only neurons and their neural circuits were responsible for the development and maintenance of neuropathic pain. In recent years, it is increasingly recognized that non-neuronal cells such as immune cells and g
Monocyte chemoattractant protein-1 affects migration of hippocampal neural progenitors following status epilepticus in rats  [cached]
Hung Yu-Wen,Lai Ming-Tsong,Tseng Yi-Jhan,Chou Chien-Chen
Journal of Neuroinflammation , 2013, DOI: 10.1186/1742-2094-10-11
Abstract: Background Epilepsy is a common brain disorder characterized by a chronic predisposition to generate spontaneous seizures. The mechanisms for epilepsy formation remain unknown. A growing body of evidence suggests the involvement of inflammatory processes in epileptogenesis. In the present study, we investigated the involvement of monocyte chemoattractant protein-1 (MCP-1) in aberrant migration of hippocampal progenitors in rats after the insult of status epilepticus (SE). Methods SE was induced with pilocarpine in Sprague–Dawley rats. Transcriptional expression of MCP-1 in the dentate gyrus (DG) was measured using quantitative real-time PCR. From 1 to 28 days after SE, the temporal profiles of MCP-1 protein expression in DG were evaluated using enzyme-linked immunosorbent assay. Chemokine (C-C motif) receptor 2 (CCR2) expression in doublecortin-positive neuronal progenitors was examined using double-labeling immunohistochemistry. The involvement of MCP-1/CCR2 signaling in aberrant neuronal progenitor migration in the epileptic hippocampus was assessed in the SE rats using a CCR2 antagonist, RS102895, and the ectopic migration of neuronal progenitors was determined using Prox1/doublecortin double immunostaining. Results After SE, MCP-1 gene was significantly upregulated and its corresponding protein expression in the DG was significantly increased on days 1 and 3. Some hilar ectopic progenitor cells of SE rats expressed the MCP-1 receptor, CCR2. Notably, the ectopic migration of neuronal progenitors into hilus was attenuated by a blockade of the MCP-1/CCR2 interaction with a selective CCR2 inhibitor, RS102895. Conclusions An increase in dentate MCP-1 is associated with seizure-induced aberrant migration of neuronal progenitors through the interaction with CCR2. The upregulation of MCP-1 after an insult of SE may play a role in the generation of epilepsy.
CCR2 Acts as Scavenger for CCL2 during Monocyte Chemotaxis  [PDF]
Silvia Volpe, Elisabetta Cameroni, Barbara Moepps, Sylvia Thelen, Tiziana Apuzzo, Marcus Thelen
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0037208
Abstract: Background Leukocyte migration is essential for effective host defense against invading pathogens and during immune homeostasis. A hallmark of the regulation of this process is the presentation of chemokines in gradients stimulating leukocyte chemotaxis via cognate chemokine receptors. For efficient migration, receptor responsiveness must be maintained whilst the cells crawl on cell surfaces or on matrices along the attracting gradient towards increasing concentrations of agonist. On the other hand agonist-induced desensitization and internalization is a general paradigm for chemokine receptors which is inconsistent with the prolonged migratory capacity. Methodology/Principal Findings Chemotaxis of monocytes was monitored in response to fluorescent CCL2-mCherry by time-lapse video microscopy. Uptake of the fluorescent agonist was used as indirect measure to follow the endogenous receptor CCR2 expressed on primary human monocytes. During chemotaxis CCL2-mCherry becomes endocytosed as cargo of CCR2, however, the internalization of CCR2 is not accompanied by reduced responsiveness of the cells due to desensitization. Conclusions/Significance During chemotaxis CCR2 expressed on monocytes internalizes with the bound chemoattractant, but cycles rapidly back to the plasma membrane to maintain high responsiveness. Moreover, following relocation of the source of attractant, monocytes can rapidly reverse their polarization axis organizing a new leading edge along the newly formed gradient, suggesting a uniform distribution of highly receptive CCR2 on the plasma membrane. The present observations further indicate that during chemotaxis CCR2 acts as scavenger consuming the chemokine forming the attracting cue.
The CCL2/CCR2 Axis Enhances Vascular Cell Adhesion Molecule-1 Expression in Human Synovial Fibroblasts  [PDF]
Yu-Min Lin, Chin-Jung Hsu, Yuan-Ya Liao, Ming-Chih Chou, Chih-Hsin Tang
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0049999
Abstract: Background Chemokine ligand 2 (CCL2), also known as monocyte chemoattractant protein-1 (MCP-1), belongs to the CC chemokine family that is associated with the disease status and outcomes of osteoarthritis (OA). Here, we investigated the intracellular signaling pathways involved in CCL2-induced vascular cell adhesion molecule-1 (VCAM-1) expression in human OA synovial fibroblasts (OASFs). Methodology/Principal Findings Stimulation of OASFs with CCL2 induced VCAM-1 expression. CCL2-mediated VCAM-1 expression was attenuated by CCR2 inhibitor (RS102895), PKCδ inhibitor (rottlerin), p38MAPK inhibitor (SB203580), and AP-1 inhibitors (curcumin and tanshinone IIA). Stimulation of cells with CCL2 increased PKCδ and p38MAPK activation. Treatment of OASFs with CCL2 also increased the c-Jun phosphorylation and c-Jun binding to the AP-1 element on the VCAM-1 promoter. Moreover, CCL2-mediated CCR2, PKCδ, p38MAPK, and AP-1 pathway promoted the adhesion of monocytes to the OASFs monolayer. Conclusions/Significance Our results suggest that CCL2 increases VCAM-1 expression in human OASFs via the CCR2, PKCδ, p38MAPK, c-Jun, and AP-1 signaling pathway. The CCL2-induced VCAM-1 expression promoted monocytes adhesion to human OASFs.
In vitro migration of cytotoxic T lymphocyte derived from a colon carcinoma patient is dependent on CCL2 and CCR2
Klara Berencsi, Pyapalli Rani, Tianqian Zhang, Laura Gross, Michael Mastrangelo, Neal J Meropol, Dorothee Herlyn, Rajasekharan Somasundaram
Journal of Translational Medicine , 2011, DOI: 10.1186/1479-5876-9-33
Abstract: To identify chemokine and chemokine receptors involved in T-cell migration toward CRC cells, we have used our previously published three-dimensional organotypic CRC culture system. Organotypic culture was initiated with a layer of fetal fibroblast cells mixed with collagen matrix in a 24 well tissue culture plate. A layer of CRC cells was placed on top of the fibroblast-collagen layer which was followed by a separating layer of fibroblasts in collagen matrix. Anti-CRC specific cytotoxic T lymphocytes (CTLs) mixed with fibroblasts in collagen matrix were placed on top of the separating layer. Excess chemokine ligand (CCL) or Abs to chemokine or chemokine receptor (CCR) were used in migration inhibition assays to identify the chemokine and the receptor involved in CTL migration.Inclusion of excess CCL2 in T-cell layer or Ab to CCL2 in separating layer of collagen fibroblasts blocked the migration of CTLs toward tumor cells and in turn significantly inhibited tumor cell apoptosis. Also, Ab to CCR2 in the separating layer of collagen and fibroblasts blocked the migration of CTLs toward tumor cells and subsequently inhibited tumor cell apoptosis. Expression of CCR2 in four additional CRC patients' lymphocytes isolated from infiltrating tumor tissues suggests their role in migration in other CRC patients.Our data suggest that CCL2 secreted by tumor cells and CCR2 receptors on CTLs are involved in migration of CTLs towards tumor. Gene therapy of tumor cells with CCL2 or CCL2/anti-tumor Ab fusion proteins may attract CTLs that potentially could inhibit tumor growth.Chemokines play an important role in immune homeostasis and immune surveillance (reviewed in [1-3]). Studies have demonstrated that chemokines influence immune reactions by regulating trafficking of dendritic cells (DC) and lymphocytes [4]. In tumor bearing individuals, the role of chemokines is paradoxical. Chemokines produced by tumor cells are known to stimulate autocrine tumor growth, progression and metastas
Possible Association between Expression of Chemokine Receptor-2 (CCR2) and Amyotrophic Lateral Sclerosis (ALS) Patients of North India  [PDF]
Pawan K. Gupta, Sudesh Prabhakar, Neel K. Sharma, Akshay Anand
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0038382
Abstract: Background and Objectives We earlier reported elevated chemokine ligand-2 (CCL2) in Indian amyotrophic lateral sclerosis (ALS) patients. We now analysed chemokine receptor-2 (CCR2), the receptor of CCL2, in these ALS patients. Methods Indian sporadic ALS patients (n = 50) were included on the basis of El Escorial criteria. Percentage (%) of CCR2 expressing peripheral blood mononuclear cells (PBMCs) was evaluated using Flow Cytometry. Real Time Polymerase Chain Reaction (PCR) was used to quantitate CCR2 mRNA expression in PBMCs. Normal controls (n = 40) were also included for comparison. Results Flow Cytometry revealed significantly reduced CCR2 expressing PBMCs in the ALS patients. We also found a significant decline in number of CCR2 expressing PBMCs in limb onset ALS when compared to bulbar onset ALS. PBMCs from ALS patients showed substantial down-regulation of CCR2 mRNA. CCR2 mRNA expression was found to be decreased among limb ALS patients as compared to bulbar onset ALS. Further, the count of CCR2+ PBMCs and CCR2 mRNA transcript in PBMCs was significantly lower in severe and moderate ALS as compared to ALS patients with mild impairments. Conclusions Downregulation of PBMCs CCR2 may indicate its etio-pathological relevance in ALS pathogenesis. Reduced PBMCs CCR2 may result in decreased infiltration of leukocytes at the site of degeneration as a compensatory response to ALS. CCR2 levels measurements in hematopoietic stem cells and estimation of comparative PBMCs count among ALS, disease controls and normal controls can unveil its direct neuroprotective role. However, the conclusions are restricted by the absence of neurological/non-neurological disease controls in the study.
Alveolar macrophages lack CCR2 expression and do not migrate to CCL2
Judy M Opalek, Naeem A Ali, Jennifer M Lobb, Melissa G Hunter, Clay B Marsh
Journal of Inflammation , 2007, DOI: 10.1186/1476-9255-4-19
Abstract: We examined the expression of these receptors in human peripheral blood monocytes and alveolar macrophages using microarray analysis, reverse-transcriptase PCR, flow cytometry and migration analyses.In contrast to peripheral blood monocytes, alveolar macrophages did not express the CCL2 receptor, CCR2, and did not migrate toward CCL2. In contrast, monocytes and freshly isolated resident alveolar macrophages both migrated towards CCL3. However, up to 6-fold more monocytes migrated toward equivalent concentrations of CCL3 than did alveolar macrophages from the same donor. While peripheral blood monocytes expressed the CCL3 receptor, CCR1, alveolar macrophages expressed the alternate CCL3 receptor, CCR5. The addition of anti-CCR5 blocking antibodies completely abrogated CCL3-induced migration in alveolar macrophages, but did not affect the migration of peripheral blood monocytes.These data support the specificity of CCL2 to selectively drive monocyte, but not alveolar macrophage recruitment to the lung and CCR5 as the primary macrophage receptor for CCL3.Peripheral blood monocytes and alveolar macrophages are similar in function, both physiologically and pathophysiologically. Because monocytes are precursors to tissue macrophages, these cells are often referenced interchangeably. However, these cells have independent functions and are differentially regulated. We hypothesized that differences in receptor expression on each cell type distinguished functional chemokine responsiveness between monocytes and alveolar macrophages.To delineate the mechanism regulating peripheral blood monocyte and alveolar macrophage recruitment to the lung, the response of these cells to CCL2 was examined. CCL2, a C-C chemokine, regulates monocyte chemotaxis [1,2], a property shared by several chemokines having adjacent cysteine residues in the N-terminus [3]. Although several chemokines influence monocyte trafficking, CCL2 appears to be critical, as mice deficient in CCL2 have decreased rec
Dysregulation in Retinal Para-Inflammation and Age-Related Retinal Degeneration in CCL2 or CCR2 Deficient Mice  [PDF]
Mei Chen,John V. Forrester,Heping Xu
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0022818
Abstract: We have shown previously that a para-inflammatory response exists at the retinal/choroidal interface in the aging eye; and this response plays an important role in maintaining retinal homeostasis under chronic stress conditions. We hypothesized that dysregulation of the para-inflammatory response may result in an overt pro-inflammatory response inducing retinal degeneration. In this study, we examined this hypothesis in mice deficient in chemokine CCL2 or its cognate receptor CCR2. CCL2- or CCR2-deficient mice developed retinal degenerative changes with age, characterized as retinal pigment epithelial (RPE) cell and photoreceptor cell death. Retinal cell death was associated with significantly more subretinal microglial accumulation and increased complement activation. In addition, monocytes from CCL2- or CCR2-deficient mice had reduced capacity for phagocytosis and chemotaxis, expressed less IL-10 but more iNOS, IL-12 and TNF-α when compared to monocytes from WT mice. Complement activation at the site of RPE cell death resulted in C3b/C3d but not C5b-9 deposition, indicating only partial activation of the complement pathway. Our results suggest that altered monocyte functions may convert the protective para-inflammatory response into an overtly harmful inflammation at the retina/choroidal interface in CCL2- or CCR2-deficient mice, leading to RPE and photoreceptor degeneration. These data support a concept whereby a protective para-inflammatory response relies upon a normally functioning innate immune system. If the innate immune system is deficient chronic stress may tip the balance towards an overt inflammatory response causing cell/tissue damage.
Differential Modulation of Retinal Degeneration by Ccl2 and Cx3cr1 Chemokine Signalling  [PDF]
Ulrich F. O. Luhmann, Clemens A. Lange, Scott Robbie, Peter M. G. Munro, Jill A. Cowing, Hannah E. J. Armer, Vy Luong, Livia S. Carvalho, Robert E. MacLaren, Frederick W. Fitzke, James W. B. Bainbridge, Robin R. Ali
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0035551
Abstract: Microglia and macrophages are recruited to sites of retinal degeneration where local cytokines and chemokines determine protective or neurotoxic microglia responses. Defining the role of Ccl2-Ccr2 and Cx3cl1-Cx3cr1 signalling for retinal pathology is of particular interest because of its potential role in age-related macular degeneration (AMD). Ccl2, Ccr2, and Cx3cr1 signalling defects impair macrophage trafficking, but have, in several conflicting studies, been reported to show different degrees of age-related retinal degeneration. Ccl2/Cx3cr1 double knockout (CCDKO) mice show an early onset retinal degeneration and have been suggested as a model for AMD. In order to understand phenotypic discrepancies in different chemokine knockout lines and to study how defects in Ccl2 and/or Cx3cr1 signalling contribute to the described early onset retinal degeneration, we defined primary and secondary pathological events in CCDKO mice. To control for genetic background variability, we compared the original phenotype with that of single Ccl2, Cx3cr1 and Ccl2/Cx3cr1 double knockout mice obtained from backcrosses of CCDKO with C57Bl/6 mice. We found that the primary pathological event in CCDKO mice develops in the inferior outer nuclear layer independently of light around postnatal day P14. RPE and vascular lesions develop secondarily with increasing penetrance with age and are clinically similar to retinal telangiectasia not to choroidal neovascularisation. Furthermore, we provide evidence that a third autosomal recessive gene causes the degeneration in CCDKO mice and in all affected re-derived lines and subsequently demonstrated co-segregation of the naturally occurring RD8 mutation in the Crb1 gene. By comparing CCDKO mice with re-derived CCl2?/?/Crb1Rd8/RD8, Cx3cr1?/?/Crb1Rd8/RD8 and CCl2?/?/Cx3cr1?/?/Crb1Rd8/RD8 mice, we observed a differential modulation of the retinal phenotype by genetic background and both chemokine signalling pathways. These findings indicate that CCDKO mice are not a model of AMD, but a model for an inherited retinal degeneration that is differentially modulated by Ccl2-Ccr2 and Cx3cl1-Cx3cr1 chemokine signalling.
The obesity and inflammatory marker haptoglobin attracts monocytes via interaction with chemokine (C-C motif) receptor 2 (CCR2)
Margherita Maffei, Marcella Funicello, Teresa Vottari, Olimpia Gamucci, Mario Costa, Simonetta Lisi, Alessandro Viegi, Osele Ciampi, Giuseppe Bardi, Paolo Vitti, Aldo Pinchera, Ferruccio Santini
BMC Biology , 2009, DOI: 10.1186/1741-7007-7-87
Abstract: We demonstrated by chemotaxis assay that Hp is able to attract chemokine (C-C motif) receptor 2 (CCR2)-transfected pre-B lymphocytes and monocytes in a dose-dependent manner. Moreover, Hp-mediated migration of monocytes is impaired by CCR2-specific inhibition or previous cell exposure to monocyte chemoattractant protein 1 (MCP1) (also known as CCR2 ligand or chemokine (C-C motif) ligand 2 (CCL2)). Downstream effects of Hp/CCR2 interaction were also investigated: flow cytometry proved that monocytes treated with Hp show reduced CCR2 expression on their surface; Hp interaction induces calcium release that is reduced upon pretreatment with CCR2 antagonist; extracellular signal-regulated kinase (ERK)1/2, a signal transducer activated by CCR2, is phosphorylated following Hp treatment and this phosphorylation is reduced when cells are pretreated with a specific CCR2 inhibitor. Consistently, blocking the ERK1/2 pathway with U0126, the selective inhibitor of the ERK upstream mitogen-activated protein (MAP)-ERK kinase (MEK), results in a dramatic reduction (by almost 100%) of the capability of Hp to induce monocyte migration.Our data show that Hp is a novel monocyte chemoattractant and that its chemotactic potential is mediated, at least in part. by its interaction with CCR2.Haptoglobin (Hp) is an acute phase protein synthesized by the liver, and its serum concentrations are elevated during inflammation. Several functions have been attributed to this protein including its ability to bind free hemoglobin, thus preventing oxidative damage, and its capacity to induce angiogenesis [1]. Hp is also expressed by murine and human white adipose tissue (WAT) and, as reported previously, its expression is induced in obesity [2,3]. According to Fain et al. [4], Hp is released both by human isolated adipocytes and the adipose tissue matrix, but not by cells of the stromal vascular fraction (SVF). This result is in agreement with the observation of do Nascimento et al. [5], who showed tha
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