Implication of CCR2 chemokine receptor in cocaine-induced sensitization.

Cocaine-induced sensitization induces long-term neuroplastic changes in the striatum. Among these, extracellular signal-regulated kinase (ERK) is a fundamental component in striatal gene and epigenetic regulation and plays an important role in reward processes. As previous studies suggested that the chemokine CCL2 enhanced striatal dopamine release and as its cognate CCR2 receptor was located in brain structures implicated in cocaine reward, we tested the hypothesis that CCR2/CCL2 could be involved in cocaine-induced behavioral response.

Lung epithelial apoptosis in influenza virus pneumonia: the role of macrophage-expressed TNF-related apoptosis-inducing ligand.

Mononuclear phagocytes have been attributed a crucial role in the host defense toward influenza virus (IV), but their contribution to influenza-induced lung failure is incompletely understood. We demonstrate for the first time that lung-recruited "exudate" macrophages significantly contribute to alveolar epithelial cell (AEC) apoptosis by the release of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in a murine model of influenza-induced pneumonia. Using CC-chemokine receptor 2-deficient (CCR2(-/-)) mice characterized by defective inflammatory macrophage recruitment, and blocking anti-CCR2 antibodies, we show that exudate macrophage accumulation in the lungs of influenza-infected mice is associated with pronounced AEC apoptosis and increased lung leakage and mortality.

Ly-6G+CCR2- myeloid cells rather than Ly-6ChighCCR2+ monocytes are required for the control of bacterial infection in the central nervous system.

Myeloid cell recruitment is a characteristic feature of bacterial meningitis. However, the cellular mechanisms important for the control of Streptococcus pneumoniae infection remain largely undefined. Previous pharmacological or genetic studies broadly depleted many myeloid cell types within the meninges, which did not allow defining the function of specific myeloid subsets.

Genes contributing to prion pathogenesis.

Prion diseases are caused by conversion of a normally folded, non-pathogenic isoform of the prion protein (PrP(C)) to a misfolded, pathogenic isoform (PrP(Sc)). Prion inoculation experiments in mice expressing homologous PrP(C) molecules on different genetic backgrounds displayed different incubation times, indicating that the conversion reaction may be influenced by other gene products. To identify genes that contribute to prion pathogenesis, we analysed incubation times of prions in mice in which the gene product was inactivated, knocked out or overexpressed.

Role of inflammation in the development of renal damage and dysfunction in angiotensin II-induced hypertension.

Angiotensin II (Ang II)-induced hypertension is associated with an inflammatory response that may contribute to the development of target organ damage. We tested the hypothesis that, in Ang II-induced hypertension, CC chemokine receptor 2 (CCR2) activation plays an important role in the development of renal fibrosis, damage, and dysfunction by causing oxidative stress, macrophage infiltration, and cell proliferation. To test this hypothesis, we used CCR2 knockout mice (CCR2-/-).

Transcellular transport of CCL2 across brain microvascular endothelial cells.

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.

CC chemokine receptor 5 influences late-stage atherosclerosis.

Members of the chemokine system, play a central role in inflammatory processes that underlie the pathogenesis of atherosclerosis and possibly, aortic valve sclerosis. Here we show that genetic inactivation of CC chemokine receptor 5 (CCR5) in the atherosclerosis-prone Apoe-/- mice (Apoe-/- Ccr5-/-) fed a normal chow or a high-fat diet (HFD) are protected against advanced atherosclerosis as well as age-associated aortic valve thickening (AAAVT)--a murine correlate of aortic valve sclerosis. Notably, human sclerotic valves contained CCR5+ cells.

Chemokine receptor CCR2 but not CCR5 or CCR6 mediates the increase in pulmonary dendritic cells during allergic airway inflammation.

Increased numbers of pulmonary dendritic cells (DCs) are recruited to the lungs during allergic airway inflammation and contribute to the maintenance of the inflammatory immune response. The chemokine receptors that directly control DC accumulation into the lungs are largely unknown. To explore this issue, we generated mixed bone marrow chimeric mice containing both wild-type and knockout cells for a given chemokine receptor.

Susceptibility of CCR5-deficient mice to genital herpes simplex virus type 2 is linked to NK cell mobilization.

Following genital herpes simplex virus type 2 (HSV-2) exposure, NK cells and T cells are mobilized to sites of infection to control viral replication and spread. The present investigation sought to determine the role of the chemokine receptor CCR5 in this process. Mice deficient in CCR5 (CCR5-/-) displayed a significant reduction in cumulative survival following infection in comparison to wild-type, HSV-2-infected controls.

MCP-1/CCR2 signalling pathway regulates hyperoxia-induced acute lung injury via nitric oxide production.

To clarify the role of the monocyte chemoattractant protein-1 (MCP-1)/C-C chemokine receptor 2 (CCR2) signalling pathway in hyperoxia-induced acute lung injury, CCR2-deficient (CCR2-/-) and wild-type (CCR2+/+) mice were exposed to 85% O(2) for up to 6 days. At day 3, body weight significantly decreased and total protein concentration in bronchoalveolar lavage fluid (BALF) was higher in CCR2-/- mice compared with CCR2+/+ mice. Cumulative survivals were significantly lower in CCR2-/- mice than in CCR2+/+ mice.

Chemokines in the MPTP model of Parkinson's disease: absence of CCL2 and its receptor CCR2 does not protect against striatal neurodegeneration.

Recent studies have invoked inflammation as a major contributor to the pathogenesis of Parkinson's disease (PD). We determined the role of members of the chemokine system, key inflammatory mediators, in PD pathogenesis. In the MPTP model of murine PD, several chemokines, including CC chemokine ligand 2 (CCL2, Monocyte Chemoattractant Protein-1) and CCL3 (Macrophage Inflammatory Protein-1alpha), were upregulated in the striatum and the ventral midbrain.

Fat accumulation with altered inflammation and regeneration in skeletal muscle of CCR2-/- mice following ischemic injury.

Chemokines recruit inflammatory cells to sites of injury, but the role of the CC chemokine receptor 2 (CCR2) during regenerative processes following ischemia is poorly understood. We studied injury, inflammation, perfusion, capillary formation, monocyte chemotactic protein-1 (MCP-1) levels, muscle regeneration, fat accumulation, and transcription factor activation in hindlimb muscles of CCR2-/- and wild-type (WT) mice following femoral artery excision (FAE). In both groups, muscle injury and restoration of vascular perfusion were similar.

Tumor necrosis factor alpha- and inducible nitric oxide synthase-producing dendritic cells are rapidly recruited to the bladder in urinary tract infection but are dispensable for bacterial clearance.

The role of dendritic cells (DC) in urinary tract infections (UTI) is unknown. These cells contribute directly to the innate defense against various viral and bacterial infections. Here, we studied their role in UTI using an experimental model induced by transurethral instillation of the uropathogenic Escherichia coli (UPEC) strain 536 into C57BL/6 mice.

Alveolar epithelial cells direct monocyte transepithelial migration upon influenza virus infection: impact of chemokines and adhesion molecules.

Influenza A virus pneumonia is characterized by severe lung injury and high mortality. Early infection elicits a strong recruitment of monocytes from the peripheral blood across the endo-/epithelial barrier into the alveolar air space. However, it is currently unclear which of the infected resident lung cell populations, alveolar epithelial cells or alveolar macrophages, elicit monocyte recruitment during influenza A virus infection.

Chemokine CC receptor 2 is important for acute control of cardiac parasitism but does not contribute to cardiac inflammation after infection with Trypanosoma cruzi.

The CC chemokine ligand 2 (CCL2) and CC chemokine receptor 2 (CCR2) are expressed in the heart after infection with Trypanosoma cruzi, suggesting that they play an important role in host defense. Infection of CCR2-deficient (CCR2(-/-)) mice with T. cruzi resulted in increased cardiac parasitism, yet the severity of cardiac inflammation was not affected.

CC chemokine receptor (CCR)-2 prevents arthritis development following infection by Mycobacterium avium.

The host factors that influence autoimmune arthritides such as rheumatoid arthritis have not been fully elucidated. We previously found that genetic inactivation of CC chemokine receptor 2 (CCR2) in the arthritis-prone DBA/1j mouse strain significantly increases the susceptibility of this strain to autoimmune arthritis induced by immunization with collagen type II (CII) and complete Freund's adjuvant (CFA). Here, we show that following intradermal infection with Mycobacterium avium, a similar arthritis phenotype was detected in Ccr2-null mice in the DBA/1j, but not in the BALB/c background.

Endotoxin induced peritonitis elicits monocyte immigration into the lung: implications on alveolar space inflammatory responsiveness.

Background: Acute peritonitis developing in response to gram-negative bacterial infection is known to act as a trigger for the development of acute lung injury which is often complicated by the development of nosocomial pneumonia. We hypothesized that endotoxin-induced peritonitis provokes recruitment of monocytes into the lungs, which amplifies lung inflammatory responses to a second hit intra-alveolar challenge with endotoxin.

Methods: Serum and lavage cytokines as well as bronchoalveolar lavage fluid cells were analyzed at different time points after intraperitoneal or intratracheal application of LPS.

CC chemokine receptor-2 deficiency attenuates oxidative stress and infarct size caused by myocardial ischemia-reperfusion in mice.

Background: Monocyte chemoattractant protein-1 (MCP-1) and its major receptor, CC chemokine receptor 2 (CCR2), have been shown to contribute to left ventricular remodeling after myocardial infarction. However, it is unknown whether CCR2 deficiency protects the myocardium after myocardial ischemia-reperfusion. The purpose of the present study was to investigate the effects of CCR2 deficiency on myocardial ischemia-reperfusion injury in mice.

Abnormal immune response of CCR5-deficient mice to ocular infection with herpes simplex virus type 1.

Ocular herpes simplex virus type 1 (HSV-1) infection elicits a strong inflammatory response that is associated with production of the beta chemokines CCL3 and CCL5, which share a common receptor, CCR5. To gain insight into the role of these molecules in ocular immune responses, the corneas of wild-type (WT) and CCR5-deficient (CCR5-/-) mice were infected with HSV-1 and inflammatory parameters were measured. In the absence of CCR5, the early infiltration of neutrophils into the cornea was diminished.

Deficiency in CCR5 but not CCR1 protects against neointima formation in atherosclerosis-prone mice: involvement of IL-10.

The chemokine RANTES has been implicated in neointimal hyperplasia after arterial injury. We analyzed the differential role of the RANTES receptors CCR1 and CCR5 by genetic deletion in apolipoprotein E-deficient mice. Deficiency in CCR5 significantly reduced neointimal area after arterial wire injury, associated with a decrease in macrophages, CD3(+) T lymphocytes, and CCR2(+) cells.

The CC chemokine receptor 5 is important in control of parasite replication and acute cardiac inflammation following infection with Trypanosoma cruzi.

Infection of susceptible mice with the Colombiana strain of Trypanosoma cruzi results in an orchestrated expression of chemokines and chemokine receptors within the heart that coincides with parasite burden and cellular infiltration. CC chemokine receptor 5 (CCR5) is prominently expressed during both acute and chronic disease, suggesting a role in regulating leukocyte trafficking and accumulation within the heart following T. cruzi infection.

Perturbation of chemokine networks by gene deletion alters the reinforcing actions of ethanol.

Microarray analysis of human alcoholic brain and cultured cells exposed to ethanol showed significant changes in expression of genes related to immune or inflammatory responses, including chemokines and chemokine receptors. To test the hypothesis that chemokines exhibit previously undiscovered pleiotropic effects important for the behavioral actions of ethanol, we studied mutant mice with deletion of the Ccr2, Ccr5, Ccl2 or Ccl3 genes. Deletion of Ccr2, Ccl2 (females) or Ccl3 in mice resulted in lower preference for alcohol and consumption of lower amounts of alcohol in a two-bottle choice test as compared with wild-type mice.

Attenuated liver tumor formation in the absence of CCR2 with a concomitant reduction in the accumulation of hepatic stellate cells, macrophages and neovascularization.

The liver parenchyma is populated by hepatocytes and several nonparenchymal cell types, including Kupffer cells and hepatic stellate cells. Both Kupffer cells and hepatic stellate cells are responsive to the chemokine CCL2, but the precise roles of CCL2 and these cells in liver tumor formation remain undefined. Hence, we investigated the effects of the lack of the major CCL2 receptor, CCR2, on liver tumor formation induced by intraportal injection of the murine colon adenocarcinoma cell line, colon 26.

Recruitment of Gr-1+ monocytes is essential for control of acute toxoplasmosis.

Circulating murine monocytes comprise two largely exclusive subpopulations that are responsible for seeding normal tissues (Gr-1-/CCR2-/CX3CR1high) or responding to sites of inflammation (Gr-1+/CCR2+/CX3CR1lo). Gr-1+ monocytes are recruited to the site of infection during the early stages of immune response to the intracellular pathogen Toxoplasma gondii. A murine model of toxoplasmosis was thus used to examine the importance of Gr-1+ monocytes in the control of disseminated parasitic infection in vivo.