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William A Kuziel - One of the best experts on this subject based on the ideXlab platform.
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transcellular transport of ccl2 across brain microvascular endothelial cells
Journal of Neurochemistry, 2008Co-Authors: Shujun Ge, David R Serwanski, William A Kuziel, Li Song, Joel S PachterAbstract:The means by which the chemokine CCL2 produced in the brain parenchyma can recruit leukocytes lying behind the highly impervious endothelium of the blood–brain barrier (BBB) has remained a paradox. As other chemokines have been evidenced to stimulate their own synthesis and release by peripheral microvascular endothelial cells, and/or undergo transcytosis in the abluminal-to-luminal direction, we determined whether CCL2 experiences similar fates across brain microvascular endothelial cells (BMEC). Using cultured BMEC as a paradigm of the BBB, it was observed that exogenous unlabeled CCL2 actually depressed the release of endogenous CCL2, and further caused diminished CCL2 mRNA levels in these cells. On the other hand, exogenous 125I-labeled CCL2 exhibited transport across BMEC in a manner that was sensitive to temperature, competition by excess unlabeled CCL2 but not unlabeled CCL3, knockdown of caveolin-1/caveolae, and elimination of the cognate CCL2 receptor CCR2. These results implied a facet of CCL2 transport by a transcellular mechanism partly involving binding of CCL2 to CCR2, and subsequent transfer to caveolae vesicles for transcytosis. This notion was supported by double-label immuno-electronmicroscopy, which revealed co-localization of caveolin-1 with exogenous CCL2, during this chemokine’s transit across BMEC. Collectively, these findings provide a rationale by which CCL2, deposited on the abluminal side of the brain microvasculature during inflammatory episodes, can be relayed across the BBB to foster leukocyte recruitment.
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chemokine receptor CCR2 involvement in skeletal muscle regeneration
The FASEB Journal, 2005Co-Authors: Gordon L Warren, William A Kuziel, Tracy Hulderman, Dawn Mishra, Xin Gao, Lyndell Millecchia, Laura Ofarrell, Petia P SimeonovaAbstract:SPECIFIC AIMSWe hypothesized that signaling through CCR2, a major receptor for monocyte chemoattractant protein-1 MCP-1 (CCL2), affects degeneration/regeneration after skeletal muscle injury via indirect and direct effects on muscle precursor cells. We characterized localization of CCR2 in regenerating muscle [freeze-injured mouse tibialis anterior (TA) muscle] and compared cellular/molecular characteristics of skeletal muscle regeneration in CCR2-deficient vs. wild-type (WT) mice.PRINCIPAL FINDINGS1. CCR2 cellular localization in injured skeletal muscleTo determine whether expression of CCR2 is localized to macrophages and/or muscle precursor cells in injured muscle, we conducted double immunostaining for CCR2 and Mac-3, a marker of activated monocytes/macrophages, or myogenin, a marker of activated and differentiating muscle precursor cells. CCR2 was found to be localized to the membrane of cells expressing cytoplasmic localized Mac-3 (Fig. 1⤻ A) or nuclear localized myogenin (Fig. 1B⤻ ), demonstrating ...
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CCR2 positive monocytes recruited to inflamed lungs downregulate local ccl2 chemokine levels
American Journal of Physiology-lung Cellular and Molecular Physiology, 2005Co-Authors: U Maus, William A Kuziel, Matthias Mack, Timothy S Blackwell, John W Christman, Sandra Wellmann, Christine Hampl, Mrigank Srivastava, Brett M Everhart, Detlef SchlondorffAbstract:The CC chemokine ligand-2 (CCL2) and its receptor CCR2 are essential for monocyte trafficking under inflammatory conditions. However, the mechanisms that determine the intensity and duration of alveolar monocyte accumulation in response to CCL2 gradients in inflamed lungs have not been resolved. To determine the potential role of CCR2-expressing monocytes in regulating alveolar CCL2 levels, we compared leukocyte recruitment kinetics and alveolar CCL2 levels in wild-type and CCR2-deficient mice in response to intratracheal LPS challenge. In wild-type mice, LPS elicited a dose- and time-dependent alveolar monocyte accumulation accompanied by low CCL2 levels in bronchoalveolar lavage fluid (BALF). In contrast, LPS-treated CCR2-deficient mice lacked alveolar monocyte accumulation, which was accompanied by relatively high CCL2 levels in BALF. Similarly, wild-type mice that were treated systemically with the blocking anti-CCR2 antibody MC21 completely lacked LPS-induced alveolar monocyte trafficking that was associated with high CCL2 levels in BALF. Intratracheal application of anti-CCR2 antibody MC21 to locally block CCR2 on both resident and recruited cells did not affect LPS-induced alveolar monocyte trafficking but led to significantly increased BALF CCL2 levels. Reciprocally bone marrow-transplanted, LPS-treated wild-type and CCR2-deficient mice showed a strict inverse relationship between alveolar monocyte recruitment and BALF CCL2 levels. In addition, freshly isolated human and mouse monocytes were capable of integrating CCL2 in vitro. LPS-induced alveolar monocyte accumulation is accompanied by monocytic CCR2-dependent consumption of CCL2 levels in the lung. This feedback loop may limit the intensity of monocyte recruitment to inflamed lungs and play a role in the maintenance of homeostasis.
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c c chemokine receptor 2 CCR2 deficiency improves bleomycin induced pulmonary fibrosis by attenuation of both macrophage infiltration and production of macrophage derived matrix metalloproteinases
The Journal of Pathology, 2004Co-Authors: Toshiyuki Okuma, William A Kuziel, Yasuhiro Terasaki, Koichi Kaikita, Hironori Kobayashi, Michio Kawasuji, Motohiro TakeyaAbstract:Macrophage infiltration is implicated in various types of pulmonary fibrosis. One important pathogenetic process associated with pulmonary fibrosis is injury to basement membranes by matrix metalloproteinases (MMPs) that are produced mainly by macrophages. In this study, C-C chemokine receptor 2-deficient (CCR2−/−) mice were used to explore the relationship between macrophage infiltration and MMP activity in the pathogenesis of pulmonary fibrosis, using the bleomycin-induced model of this disease process. CCR2 is the main (if not only) receptor for monocyte chemoattractant protein-1/C-C chemokine ligand 2 (MCP-1/CCL2), which is a critical mediator of macrophage trafficking, and CCR2 −/− mice demonstrate defective macrophage migration. Pulmonary fibrosis was induced in CCR2−/− and wild-type (CCR2+/+) mice by intratracheal instillation of bleomycin. No significant differences in the total protein concentration in bronchoalveolar lavage (BAL) fluid, or in the degree of histological lung inflammation, were observed in the two groups until day 7. Between days 3 and 21, however, BAL fluid from CCR2−/− mice contained fewer macrophages than BAL fluid from CCR2+/+ mice. Gelatin zymography of BAL fluid and in situ zymography revealed reduced gelatinolytic activity in CCR2−/− mice. Immunocytochemical staining showed weaker expression of MMP-2 and MMP-9 in macrophages in BAL fluid from CCR2−/− mice at day 3. Gelatin zymography of protein extracted from alveolar macrophages showed reduced gelatinolytic activity of MMP-2 and MMP-9 in CCR2−/− mice. At days 14 and 21, lung remodelling and the hydroxyproline content of lung tissues were significantly reduced in CCR2−/− mice. These results suggest that the CCL2/CCR2 functional pathway is involved in the pathogenesis of bleomycin-induced pulmonary fibrosis and that CCR2 deficiency may improve the outcome of this disease by regulating macrophage infiltration and macrophage-derived MMP-2 and MMP-9 production. Copyright © 2004 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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crucial role of the ccl2 CCR2 axis in neointimal hyperplasia after arterial injury in hyperlipidemic mice involves early monocyte recruitment and ccl2 presentation on platelets
Circulation Research, 2004Co-Authors: Andreas Schober, William A Kuziel, Elisa A Liehn, Alma Zernecke, Philipp Von Hundelshausen, Sandra Knarren, Christian WeberAbstract:Monocyte chemoattractant protein-1 (also known as CC chemokine ligand 2 [CCL2]) and its receptor CC chemokine receptor 2 (CCR2) play a central role in the inflammatory response and neointimal formation after vascular injury. In the context of hyperlipidemia, this appears to involve neointimal monocyte infiltration. Hence, we investigated the function of the CCL2/CCR2 axis in early monocyte recruitment to injured arteries. Wire-induced injury of the carotid artery in apoE−/− mice caused a rapid increase of JE/CCL2 protein in the vessel wall peaking at 24 hours after injury, whereas serum JE/CCL2 was increased solely at 6 hours and blood cell-associated levels were unaltered, as demonstrated by enzyme-linked immunosorbent assay. Immunohistochemistry revealed intense staining for JE/CCL2 in smooth muscle cells (SMCs) and in association with platelets adherent to the denuded vessel wall 24 hours after injury. In vitro, exogenous or SMC-derived JE/CCL2 binds to the platelet surface and triggers monocyte arrest...
Wolfgang Schaper - One of the best experts on this subject based on the ideXlab platform.
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collateral artery growth arteriogenesis after experimental arterial occlusion is impaired in mice lacking cc chemokine receptor 2
Circulation Research, 2004Co-Authors: Matthias Heil, Shawn Wagner, Tibor Ziegelhoeffer, Armin Helisch, Silvia Tribulova, Georg Bachmann, Sandra L. Martin, William A Kuziel, Wolfgang SchaperAbstract:Arteriogenesis has been associated with the presence of monocytes/macrophages within the collateral vessel wall. Induced macrophage migration in vivo is driven by the binding of monocyte chemoattractant protein-1 (MCP-1, or CCL2 in the new nomenclature) to the CCR2-chemokine receptor on macrophages. To determine whether the CCL2-CCR2 signaling pathway is involved in the accumulation of macrophages in growing collateral vessels, we used mice that are deficient in CCR2 in a model of experimental arterial occlusion and collateral vessel growth. In an in vitro CCL2-driven chemotaxis assay, mononuclear cells isolated from wild-type BALB/c mice exhibited CCL2 concentration–dependent migration, whereas this migration was abolished in cells from CCR2−/− mice on a BALB/c genetic background. In vivo, blood flow recovery as measured by laser Doppler (LDI) and MRI (MRI) was impaired in CCR2−/− mice on either the BALB/c or C57BL/6 genetic backgrounds. Three weeks after femoral artery ligation, LDI perfusion ratio of o...
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collateral artery growth arteriogenesis after experimental arterial occlusion is impaired in mice lacking cc chemokine receptor 2
Circulation Research, 2004Co-Authors: Matthias Heil, Shawn Wagner, Tibor Ziegelhoeffer, Armin Helisch, Silvia Tribulova, Georg Bachmann, Sandra L. Martin, William A Kuziel, Borja Fernandez, Wolfgang SchaperAbstract:Arteriogenesis has been associated with the presence of monocytes/macrophages within the collateral vessel wall. Induced macrophage migration in vivo is driven by the binding of monocyte chemoattractant protein-1 (MCP-1, or CCL2 in the new nomenclature) to the CCR2-chemokine receptor on macrophages. To determine whether the CCL2-CCR2 signaling pathway is involved in the accumulation of macrophages in growing collateral vessels, we used mice that are deficient in CCR2 in a model of experimental arterial occlusion and collateral vessel growth. In an in vitro CCL2-driven chemotaxis assay, mononuclear cells isolated from wild-type BALB/c mice exhibited CCL2 concentration-dependent migration, whereas this migration was abolished in cells from CCR2(-/-) mice on a BALB/c genetic background. In vivo, blood flow recovery as measured by laser Doppler (LDI) and MRI (MRI) was impaired in CCR2(-/-) mice on either the BALB/c or C57BL/6 genetic backgrounds. Three weeks after femoral artery ligation, LDI perfusion ratio of operated versus nonoperated distal hindlimb in BALB/c wild-type mice increased to 0.45+/-0.06 and in CCR2(-/-) animals only to 0.21+/-0.03 (P<0.01). In C57BL/6 mice, ratio increased to 0.96+/-0.09 and 0.85+/-0.08 (P<0.05), respectively. MRI at 3 weeks (0.76+/-0.06 versus 0.62+/-0.01; P<0.05) and hemoglobin oxygen saturation measurements confirmed these findings. Active foot movement score significantly decreased and gastrocnemius muscle atrophy was significantly greater in CCR2(-/-) mice. Morphometric analysis showed a lesser increase in collateral vessel diameters in CCR2(-/-) mice. Importantly, the number of invaded monocytes/macrophages in the perivascular space of collateral arteries of CCR2(-/-) animals was dramatically reduced in comparison to wild-type mice. In conclusion, our results demonstrate that the CCR2 signaling pathway is essential for efficient collateral artery growth.
Eroboghene E Ubogu - One of the best experts on this subject based on the ideXlab platform.
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CCR2 gene deletion and pharmacologic blockade ameliorate a severe murine experimental autoimmune neuritis model of guillain barre syndrome p1 062
Neurology, 2014Co-Authors: Eroboghene E UboguAbstract:OBJECTIVE: To deduce molecular determinants and signaling pathways responsible for leukocyte trafficking during peripheral neuroinflammation aimed towards efficacious drug discovery. BACKGROUND: Current treatments for GBS are non-specific and partly efficacious. An observational study suggested a pathogenic role for chemokine ligand/receptor CCL2/CCR2 in the AIDP variant of GBS. Chemokine receptors, being G-protein coupled, are amenable anti-inflammatory targets. DESIGN/METHODS: A severe murine experimental autoimmune neuritis (sm-EAN) model that mimics AIDP was utilized. Sm-EAN was induced in 8-12 week old female SJL CCR2 knockout (CCR2 KO), heterozygote (CCR2 HT) and wild type (CCR2 WT) mice. Daily neuromuscular severity scores were recorded. In vitro and in vivo splenocyte proliferation and cytokine expression, and sciatic nerve Toll-like receptor (TLR) 2, TLR4 and CCL2 expression assays were performed to evaluate systemic and local innate immune activation at disease onset. Motor nerve electrophysiology and sciatic nerve histology were also performed to characterize the inflammatory neuropathy. Mimicking a drug trial, 20 mg/kg CCR2 antagonist, RS 102895 was administered daily for 5 days to female SJL CCR2 WT mice following sm-EAN disease onset, with efficacy directly compared to 400 mg/kg human IVIg. RESULTS: CCR2 KO mice were resistant to sm-EAN compared to CCR2 WT and CCR2 HT mice, associated with significantly reduced inflammatory demyelination. Partial gene deletion did not confer any protection against sm-EAN. CCR2 KO mice demonstrated similar splenocyte activation or proliferation profiles, as well as TLR2, TLR4 and CCL2 expression to CCR2 WT or CCR2 HT mice, implying a direct role for CCR2 in sm-EAN pathogenesis. CCR2 drug antagonism resulted in rapid, near complete recovery from sm-EAN following disease onset; being significantly more efficacious than IVIg. CONCLUSIONS: CCR2 mediates pathogenic monocyte trafficking into peripheral nerves, with consequential demyelination in sm-EAN. CCR2 is amenable to pharmacologic blockade, making it a plausible target for novel AIDP therapies. Study Supported by: Baylor College of Medicine New Investigator Start-Up funds and NIH/NINDS Grant R21 NS078226 Disclosure: Dr. Ubogu has nothing to disclose.
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CCR2 gene deletion and pharmacologic blockade ameliorate a severe murine experimental autoimmune neuritis model of guillain barre syndrome
PLOS ONE, 2014Co-Authors: Furong Yuan, Nejla Yosef, Chetan Lakshmana Reddy, Ailing Huang, Sharon Chiang, Hafiza Rahman Tithi, Eroboghene E UboguAbstract:The molecular determinants and signaling pathways responsible for hematogenous leukocyte trafficking during peripheral neuroinflammation are incompletely elucidated. Chemokine ligand/receptor pair CCL2/CCR2 has been pathogenically implicated in the acute inflammatory demyelinating polyradiculoneuropathy variant of Guillain-Barre syndrome (GBS). We evaluated the role of CCR2 in peripheral neuroinflammation utilizing a severe murine experimental autoimmune neuritis (sm-EAN) model. Sm-EAN was induced in 8–12 week old female SJL CCR2 knockout (CCR2KO), heterozygote (CCR2HT) and wild type (CCR2WT) mice, and daily neuromuscular severity scores and weights recorded. In vitro and in vivo splenocyte proliferation and cytokine expression assays, and sciatic nerve Toll-like receptor (TLR) 2, TLR4 and CCL2 expression assays were performed to evaluate systemic and local innate immune activation at disease onset. Motor nerve electrophysiology and sciatic nerve histology were also performed to characterize the inflammatory neuropathy at expected peak severity. To further determine the functional relevance of CCR2 in sm-EAN, 20 mg/kg CCR2 antagonist, RS 102895 was administered daily for 5 days to a cohort of CCR2WT mice following sm-EAN disease onset, with efficacy compared to 400 mg/kg human intravenous immunoglobulin (IVIg). CCR2KO mice were relatively resistant to sm-EAN compared to CCR2WT and CCR2HT mice, associated with attenuated peripheral nerve demyelinating neuritis. Partial CCR2 gene deletion did not confer any protection against sm-EAN. CCR2KO mice demonstrated similar splenocyte activation or proliferation profiles, as well as TLR2, TLR4 and CCL2 expression to CCR2WT or CCR2HT mice, implying a direct role for CCR2 in sm-EAN pathogenesis. CCR2 signaling blockade resulted in rapid, near complete recovery from sm-EAN following disease onset. RS 102895 was significantly more efficacious than IVIg. CCR2 mediates pathogenic hematogenous monocyte trafficking into peripheral nerves, with consequential demyelination in sm-EAN. CCR2 is amenable to pharmacologic blockade, making it a plausible drug target for GBS.
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Modulating CCR2 and CCL2 at the blood-brain barrier: relevance for multiple sclerosis pathogenesis.
Brain : a journal of neurology, 2005Co-Authors: Don Mahad, Melissa K Callahan, Katherine A Williams, Eroboghene E Ubogu, Pia Kivisäkk, Barbara Tucky, Grahame Kidd, Gillian A Kingsbury, Ansi Chang, Robert J FoxAbstract:Chemokines and chemokine receptors play a key role in the transmigration of leucocytes across the blood-brain barrier (BBB). CCR2 is the major receptor for CCL2, a potent monocyte and T cell chemoattractant. CCR2 and CCL2 have been consistently associated with a pathogenic role in experimental autoimmune encephalomyelitis, using knockout and transgenic mice, neutralizing antibodies, peptide antagonists and DNA vaccination. However, the significance of CCL2 and CCR2 in multiple sclerosis is enigmatic, because CCL2 levels are consistently decreased in the CSF of patients with this disease and other chronic neuroinflammatory conditions, despite abundant expression within lesional multiple sclerosis tissues. This study used an in vitro BBB model to test the hypothesis that CCL2 is removed from the extracellular fluid by CCR2-positive migrating cells as they cross the BBB, resulting in decreased CSF CCL2 levels. We showed that CCR2-positive T cells and monocytes migrated selectively across the in vitro BBB, and that CCL2 on the abluminal (tissue) side was consumed by migrating T cells and monocytes. Next, we used a new anti-CCR2 antibody to show that CCR2-positive mononuclear inflammatory cells could be readily detected in appropriate positive control tissues, but that CCR2+ cells were very infrequently found in multiple sclerosis lesions. We then showed that CCR2 receptor density on T cells and monocytes was specifically downregulated upon in vitro BBB transmigration in response to CCL2, but not irrelevant chemokines. These findings document a novel strategy for analysing chemokine receptor function in inflammatory CNS disease, and support the hypothesis that CCL2 is consumed by migrating inflammatory cells, which downregulate CCR2, as they cross the BBB.
Sarah F. Leibowitz - One of the best experts on this subject based on the ideXlab platform.
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ccl2 CCR2 system in neuroepithelial radial glia progenitor cells involvement in stimulatory sexually dimorphic effects of maternal ethanol on embryonic development of hypothalamic peptide neurons
Journal of Neuroinflammation, 2020Co-Authors: Guo-qing Chang, Olga Karatayev, Devi Sai Sri Kavya Boorgu, Sarah F. LeibowitzAbstract:Clinical and animal studies show that alcohol consumption during pregnancy produces lasting behavioral disturbances in offspring, including increased alcohol drinking, which are linked to inflammation in the brain and disturbances in neurochemical systems that promote these behaviors. These include the neuropeptide, melanin-concentrating hormone (MCH), which is mostly expressed in the lateral hypothalamus (LH). Maternal ethanol administration at low-to-moderate doses, while stimulating MCH neurons without affecting apoptosis or gliogenesis, increases in LH the density of neurons expressing the inflammatory chemokine C-C motif ligand 2 (CCL2) and its receptor CCR2 and their colocalization with MCH. These neural effects associated with behavioral changes are reproduced by maternal CCL2 administration, reversed by a CCR2 antagonist, and consistently stronger in females than males. The present study investigates in the embryo the developmental origins of this CCL2/CCR2-mediated stimulatory effect of maternal ethanol exposure on MCH neurons. Pregnant rats from embryonic day 10 (E10) to E15 during peak neurogenesis were orally administered ethanol at a moderate dose (2 g/kg/day) or peripherally injected with CCL2 or CCR2 antagonist to test this neuroimmune system’s role in ethanol’s actions. Using real-time quantitative PCR, immunofluorescence histochemistry, in situ hybridization, and confocal microscopy, we examined in embryos at E19 the CCL2/CCR2 system and MCH neurons in relation to radial glia progenitor cells in the hypothalamic neuroepithelium where neurons are born and radial glia processes projecting laterally through the medial hypothalamus that provide scaffolds for neuronal migration into LH. We demonstrate that maternal ethanol increases radial glia cell density and their processes while stimulating the CCL2/CCR2 system and these effects are mimicked by maternal administration of CCL2 and blocked by a CCR2 antagonist. While stimulating CCL2 colocalization with radial glia and neurons but not microglia, ethanol increases MCH neuronal number near radial glia cells and making contact along their processes projecting into LH. Further tests identify the CCL2/CCR2 system in NEP as a primary source of ethanol’s sexually dimorphic actions. These findings provide new evidence for how an inflammatory chemokine pathway functions within neuroprogenitor cells to mediate ethanol’s long-lasting, stimulatory effects on peptide neurons linked to adolescent drinking behavior.
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third ventricular injection of ccl2 in rat embryo stimulates ccl2 CCR2 neuroimmune system in neuroepithelial radial glia progenitor cells relation to sexually dimorphic stimulatory effects on peptide neurons in lateral hypothalamus
Neuroscience, 2020Co-Authors: Guo-qing Chang, Olga Karatayev, Devi Sai Sri Kavya Boorgu, Sarah F. LeibowitzAbstract:Abstract Clinical and animal studies show maternal alcohol consumption during pregnancy causes in offspring persistent alterations in neuroimmune and neurochemical systems known to increase alcohol drinking and related behaviors. Studies in lateral hypothalamus (LH) demonstrate in adolescent offspring that maternal oral administration of ethanol stimulates the neuropeptide, melanin-concentrating hormone (MCH), together with the inflammatory chemokine C–C motif ligand 2 (CCL2) and its receptor CCR2 which are increased in most MCH neurons. These effects, consistently stronger in females than males, are detected in embryos, not only in LH but hypothalamic neuroepithelium (NEP) along the third ventricle where neurons are born and CCL2 is stimulated within radial glia progenitor cells and their laterally projecting processes that facilitate MCH neuronal migration toward LH. With ethanol’s effects similarly produced by maternal peripheral CCL2 administration and blocked by CCR2 antagonist, we tested here using in utero intracerebroventricular (ICV) injections whether CCL2 acts locally within the embryonic NEP. After ICV injection of CCL2 (0.1 µg/µl) on embryonic day 14 (E14) when neurogenesis peaks, we observed in embryos just before birth (E19) a significant increase in endogenous CCL2 within radial glia cells and their processes in NEP. These auto-regulatory effects, evident only in female embryos, were accompanied by increased density of CCL2 and MCH neurons in LH, more strongly in females than males. These results support involvement of embryonic CCL2/CCR2 neuroimmune system in radial glia progenitor cells in mediating sexually dimorphic effects of maternal challenges such as ethanol on LH MCH neurons that colocalize CCL2 and CCR2.
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ccl2 CCR2 chemokine system in embryonic hypothalamus involvement in sexually dimorphic stimulatory effects of prenatal ethanol exposure on peptide expressing neurons
Neuroscience, 2020Co-Authors: Guo-qing Chang, Olga Karatayev, Devi Sai Sri Kavya Boorgu, Sarah F. LeibowitzAbstract:Abstract Maternal consumption of ethanol during pregnancy is known to increase the offspring’s risk for developing alcohol use disorders and associated behavioral disturbances. Studies in adolescent and adult animals suggest the involvement of neuroimmune and neurochemical systems in the brain that control these behaviors. To understand the origin of these effects during early developmental stages, we examined in the embryo and neonate the effects of maternal intraoral administration of ethanol (2 g/kg/day) from embryonic day 10 (E10) to E15 on the inflammatory chemokine C-C motif ligand 2 (CCL2) and its receptor CCR2 in a specific, dense population of neurons in the lateral hypothalamus (LH), where they are closely related to an orexigenic neuropeptide, melanin-concentrating hormone (MCH), known to promote ethanol consumption and related behaviors. We found that prenatal ethanol exposure increases the expression and density of CCL2 and CCR2 cells along with MCH neurons in the LH and the colocalization of CCL2 with MCH. We also discovered that these effects are sexually dimorphic, consistently stronger in female embryos, and are blocked by maternal administration of a CCL2 antibody (1 and 5 µg/day, i.p., E10-E15) that neutralizes endogenous CCL2 and of a CCR2 antagonist INCB3344 (1 mg/day, i.p., E10-E15) that blocks CCL2′s main receptor. These results, which in the embryo anatomically and functionally link the CCL2/CCR2 system to MCH neurons in the LH, suggest an important role for this neuroimmune system in mediating ethanol’s sexually dimorphic, stimulatory effect on MCH neurons that may promote higher level of alcohol consumption described in females.
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hypothalamic ccl2 CCR2 chemokine system role in sexually dimorphic effects of maternal ethanol exposure on melanin concentrating hormone and behavior in adolescent offspring
The Journal of Neuroscience, 2018Co-Authors: Guo-qing Chang, Olga Karatayev, Viktoriya Halkina, Jonathan Edelstien, Estefania Ramirez, Sarah F. LeibowitzAbstract:Clinical and animal studies show that ethanol exposure and inflammation during pregnancy cause similar behavioral disturbances in the offspring. While ethanol is shown to stimulate both neuroimmune and neurochemical systems in adults, little is known about their anatomical relationship in response to ethanol in utero and whether neuroimmune factors mediate ethanol's effects on neuronal development and behavior in offspring. Here we examined in female and male adolescent rats a specific population of neurons concentrated in lateral hypothalamus, which coexpress the inflammatory chemokine C-C motif ligand 2 (CCL2) or its receptor CCR2 with the orexigenic neuropeptide, melanin-concentrating hormone (MCH), that promotes ethanol drinking behavior. We demonstrate that maternal administration of ethanol (2 g/kg/d) from embryonic day 10 (E10) to E15, while having little impact on glia, stimulates expression of neuronal CCL2 and CCR2, increases density of both large CCL2 neurons colocalizing MCH and small CCL2 neurons surrounding MCH neurons, and stimulates ethanol drinking and anxiety in adolescent offspring. We show that these neuronal and behavioral changes are similarly produced by maternal administration of CCL2 (4 or 8 μg/kg/d, E10-E15) and blocked by maternal administration of a CCR2 antagonist INCB3344 (1 mg/kg/d, E10-E15), and these effects of ethanol and CCL2 are sexually dimorphic, consistently stronger in females. These results suggest that this neuronal CCL2/CCR2 system closely linked to MCH neurons has a role in mediating the effects of maternal ethanol exposure on adolescent offspring and contributes to the higher levels of adolescent risk factors for alcohol use disorders described in women.SIGNIFICANCE STATEMENT Ethanol consumption and inflammatory agents during pregnancy similarly increase alcohol intake and anxiety in adolescent offspring. To investigate how neurochemical and neuroimmune systems interact to mediate these disturbances, we examined a specific population of hypothalamic neurons coexpressing the inflammatory chemokine CCL2 and its receptor CCR2 with the neuropeptide, melanin-concentrating hormone. We demonstrate in adolescent offspring that maternal administration of CCL2, like ethanol, stimulates these neurons and increases ethanol drinking and anxiety, and these effects of ethanol are blocked by maternal CCR2 antagonist and consistently stronger in females. This suggests that neuronal chemokine signaling linked to neuropeptides mediates effects of maternal ethanol exposure on adolescent offspring and contributes to higher levels of adolescent risk factors for alcohol use disorders in women.
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stimulatory role of the chemokine ccl2 in the migration and peptide expression of embryonic hypothalamic neurons
Journal of Neurochemistry, 2014Co-Authors: Kinning Poon, Jessica R Barson, Sarah F. LeibowitzAbstract:Neuroinflammation is a feedback mechanism against infection, with recent studies suggesting a neuromodulatory role. The chemokine, C-C chemokine ligand 2 (CCL2), and its receptor, C-C chemokine receptor type 2 (CCR2), affect neuromodulation and migration in response to damage. Although CCL2 co-localizes with neuropeptides in the hypothalamus that control voluntary behavior, the unction of CCL2/CCR2 is unknown. This led us to consider the possibility that CCL2 acting through CCR2, under natural conditions, may affect the migration and peptide levels of hypothalamic neurons that control voluntary behavior. This study used primary embryonic hypothalamic neurons to examine the effect of CCL2 on migratory behavior and on levels of the peptides, enkephalin (ENK) and galanin (GAL). Treatment with CCL2 led to a significant, dose-dependent increase in the number of migrated neurons and an increase in the velocity and distance traveled. CCL2 also significantly increased the number of ENK-expressing and CCR2/ENK co-expressing neurons and the percentage of neurons that contain higher levels of ENK. Lastly, CCL2 produced a dose-dependent increase in expression of ENK and GAL. These results provide evidence for a stimulatory effect of CCL2 on embryonic hypothalamic neurons involving changes in migratory behavior, expression, and synthesis of neuropeptides that function in controlling behavior.
Matthias Heil - One of the best experts on this subject based on the ideXlab platform.
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collateral artery growth arteriogenesis after experimental arterial occlusion is impaired in mice lacking cc chemokine receptor 2
Circulation Research, 2004Co-Authors: Matthias Heil, Shawn Wagner, Tibor Ziegelhoeffer, Armin Helisch, Silvia Tribulova, Georg Bachmann, Sandra L. Martin, William A Kuziel, Wolfgang SchaperAbstract:Arteriogenesis has been associated with the presence of monocytes/macrophages within the collateral vessel wall. Induced macrophage migration in vivo is driven by the binding of monocyte chemoattractant protein-1 (MCP-1, or CCL2 in the new nomenclature) to the CCR2-chemokine receptor on macrophages. To determine whether the CCL2-CCR2 signaling pathway is involved in the accumulation of macrophages in growing collateral vessels, we used mice that are deficient in CCR2 in a model of experimental arterial occlusion and collateral vessel growth. In an in vitro CCL2-driven chemotaxis assay, mononuclear cells isolated from wild-type BALB/c mice exhibited CCL2 concentration–dependent migration, whereas this migration was abolished in cells from CCR2−/− mice on a BALB/c genetic background. In vivo, blood flow recovery as measured by laser Doppler (LDI) and MRI (MRI) was impaired in CCR2−/− mice on either the BALB/c or C57BL/6 genetic backgrounds. Three weeks after femoral artery ligation, LDI perfusion ratio of o...
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collateral artery growth arteriogenesis after experimental arterial occlusion is impaired in mice lacking cc chemokine receptor 2
Circulation Research, 2004Co-Authors: Matthias Heil, Shawn Wagner, Tibor Ziegelhoeffer, Armin Helisch, Silvia Tribulova, Georg Bachmann, Sandra L. Martin, William A Kuziel, Borja Fernandez, Wolfgang SchaperAbstract:Arteriogenesis has been associated with the presence of monocytes/macrophages within the collateral vessel wall. Induced macrophage migration in vivo is driven by the binding of monocyte chemoattractant protein-1 (MCP-1, or CCL2 in the new nomenclature) to the CCR2-chemokine receptor on macrophages. To determine whether the CCL2-CCR2 signaling pathway is involved in the accumulation of macrophages in growing collateral vessels, we used mice that are deficient in CCR2 in a model of experimental arterial occlusion and collateral vessel growth. In an in vitro CCL2-driven chemotaxis assay, mononuclear cells isolated from wild-type BALB/c mice exhibited CCL2 concentration-dependent migration, whereas this migration was abolished in cells from CCR2(-/-) mice on a BALB/c genetic background. In vivo, blood flow recovery as measured by laser Doppler (LDI) and MRI (MRI) was impaired in CCR2(-/-) mice on either the BALB/c or C57BL/6 genetic backgrounds. Three weeks after femoral artery ligation, LDI perfusion ratio of operated versus nonoperated distal hindlimb in BALB/c wild-type mice increased to 0.45+/-0.06 and in CCR2(-/-) animals only to 0.21+/-0.03 (P<0.01). In C57BL/6 mice, ratio increased to 0.96+/-0.09 and 0.85+/-0.08 (P<0.05), respectively. MRI at 3 weeks (0.76+/-0.06 versus 0.62+/-0.01; P<0.05) and hemoglobin oxygen saturation measurements confirmed these findings. Active foot movement score significantly decreased and gastrocnemius muscle atrophy was significantly greater in CCR2(-/-) mice. Morphometric analysis showed a lesser increase in collateral vessel diameters in CCR2(-/-) mice. Importantly, the number of invaded monocytes/macrophages in the perivascular space of collateral arteries of CCR2(-/-) animals was dramatically reduced in comparison to wild-type mice. In conclusion, our results demonstrate that the CCR2 signaling pathway is essential for efficient collateral artery growth.