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PubMed2006

The absence of CCL2 expression in cervical carcinoma is associated with increased survival and loss of heterozygosity at 17q11.2.

To determine whether CCL2 mRNA expression is beneficial or detrimental for cervical cancer patients, the association between the expression of this molecule by cervical tumour cells, the number of tumour-associated macrophages, and clinicopathological parameters such as recurrence, relapse-free survival, and overall patient survival was investigated. In cervical cancer samples from 93 untreated cervical cancer patients, the CCL2 mRNA expression level was quantified using RNA in situ hybridization and verified using real-time quantitative RT-PCR. The number of tumour-associated macrophages was determined using immunohistochemistry. Furthermore, the study investigated whether lack of CCL2 expression was due to genetic alterations near the 17q11.2 (CCL2 genomic) region. CCL2 mRNA expression by cervical tumour cells was associated with the number of tumour-associated macrophages (p < 0.001). Lack of CCL2 mRNA expression (15 samples; 16%) was associated with increased cumulative relapse-free survival (log rank test, p = 0.030), increased cumulative overall survival (log rank test, p = 0.024), less post-operative surgery, reduced local and distant recurrence, reduced vascular invasion, and smaller tumour size (<40 mm). The absence of CCL2 mRNA expression corresponded with loss of heterozygosity (LOH) at 17q11.2 in five of six samples. The increased cumulative relapse-free survival and cumulative overall survival of cervical cancer patients lacking tumour cell-associated CCL2 mRNA suggest that the tumour-associated macrophages support tumour progression, presumably by promoting angiogenesis and production of growth factors.

Biomarkers, Tumor↗
PubMed2026

MYBL2 promotes malignant phenotypes and M2-like macrophage polarization through CCL2 in non-small cell lung cancer.

Hub genes associated with non-small cell lung cancer (NSCLC) were identified through bioinformatics screening. In vitro experiments analyzed the potential mechanisms by which these genes regulate tumor malignant phenotypes and macrophage polarization. Differentially expressed genes were identified from The Cancer Genome Atlas (TCGA)-NSCLC and GSE32175 datasets, followed by protein-protein interaction (PPI) network analysis to screen hub genes. The effects of MYB Proto-Oncogene Like 2 (MYBL2) on NSCLC progression and macrophage polarization were evaluated using in vitro models. The regulatory relationship between MYBL2 and C-C motif chemokine ligand 2 (CCL2) was investigated by Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays, and rescue experiments were performed to validate the role of the MYBL2-CCL2 axis. Bioinformatics screening identified BUB1B, CDCA2 and MYBL2 as key hub genes with high expression in NSCLC, among which MYBL2 was significantly upregulated in NSCLC cells. Functional experiments confirmed that MYBL2 silencing markedly inhibited the malignant proliferation, migration and invasion of NSCLC cells. Tumor cell MYBL2 knockdown effectively reversed M2-like polarization and promoted M1-like polarization in the co-culture system. Mechanistically, MYBL2 directly bound to the CCL2 promoter region to enhance CCL2 transcriptional activity and upregulate CCL2 expression in NSCLC cells. Exogenous CCL2 supplementation significantly rescued the inhibitory effect of MYBL2 knockdown on macrophage M2-like polarization, verifying the mediating role of CCL2 in this regulatory axis. MYBL2 is strongly expressed in NSCLC cells and is associated with enhanced malignant phenotypes. It may affect macrophage M2-like polarization by upregulating CCL2, thus participating in NSCLC immune microenvironment remodeling.

CCL2↗
PubMed2005

The expression of CCL2 by T lymphocytes of mammary tumor bearers: role of tumor-derived factors.

Tumor-associated chemokines, including CC chemokine ligand 2/monocyte chemoattractant protein-1 (CCL2), are thought to play many roles in cancer progression. Here we demonstrate the novel finding that during growth of the D1-7,12-dimethylbenzanthracene-3 mammary tumor in BALB/c mice, there is a dramatic up-regulation of CCL2 in splenic T cells at both the mRNA and protein levels upon stimulation. Of particular relevance is the finding that tumor-infiltrating T cells also produce high levels of CCL2. While a variety of tumor cell lines have been found to produce CCL2, we found no detectable levels of CCL2 protein in supernatants of the cultured mammary tumor cells. Investigation of the mechanisms involved in CCL2 induction showed that treatment of splenic T cells with the tumor-derived factors GM-CSF and phosphatidyl serine (PS) resulted in increased CCL2 production. This increased production may be involved in the downregulation of IFN-gamma by the T cells of tumor-bearing mice previously reported in this model, as treatment of splenic T lymphocytes with CCL2 resulted in a decreased secretion of IFN-gamma by those cells.

Animals↗
PubMed2006

Host chemokine (C-C motif) ligand-2 (CCL2) is differentially regulated in HIV type 1 (HIV-1)-infected individuals.

Several cytokines and chemokines including chemokine (C-C motif) ligand-2 (CCL2) are induced in HIV-1 infection. However, the impact of HIV-1 viremia on CCL2 regulation is largely unknown. We utilized a DNA oligonucleotide microarray covering 110 inflammatory genes. Five genes were induced by at least 2-fold in PBMCs of HIV-1 viremic (>100,000 RNA copies ml(-1)) as compared with aviremic (<50 RNA copies ml(-1)) individuals. These genes were CCL2, CXC chemokine ligand-10, IFN-gamma, GTP-cyclohydrolase-1 and C-C chemokine receptor-1. In addition to microarray data verification by real-time PCR, analysis of independent patient samples revealed a similar expression pattern. CCL2 was the most strongly regulated gene at mRNA level and its serum concentration was significantly elevated in viremic compared with aviremic and HIV-1 seronegative controls, indicating a positive correlation between viremia and CCL2. Flow cytometric studies demonstrated a higher percentage of CCL2-expressing CD14(+) monocytes in viremic compared with aviremic individuals. These results suggest a highly restricted modulation of host inflammatory gene response by HIV. Genes up-regulated in the viremic state, in particular CCL2, presumably serve as potential enhancing factors in HIV-1 replication, represented by high viral load in HIV-1 viremic patients. Inhibition of increased CCL2 production could provide a new therapeutic intervention in HIV-1 infection.

Antiretroviral Therapy, Highly Active↗
PubMed2004

Transgenic expression of CCL2 in the central nervous system prevents experimental autoimmune encephalomyelitis.

CC chemokine ligand 2 (CCL2)/monocyte chemotactic protein-1, a member of the CC chemokine family, is a chemoattractant for monocytes and T cells through interaction with its receptor CCR2. In the present study, we examined a T helper cell type 1 (Th1)-dependent disease, proteolipid protein-induced experimental autoimmune encephalomyelitis, in a transgenic mouse line that constitutively expressed low levels of CCL2 in the central nervous system (CNS) under control of the astrocyte-specific glial fibrillary acidic protein promoter. CCL2 transgenic mice developed significantly milder clinical disease than littermate controls. As determined by flow cytometry, mononuclear cell infiltrates in the CNS tissues of CCL2 transgenic and littermate-control mice contained equal numbers of CD4+ and CD8+ T cells, and the CCL2 transgenic mice showed an enhanced number of CNS-infiltrating monocytes. CNS antigen-specific T cells from CCL2 transgenic mice produced markedly less interferon-gamma. Overexpression of CCL2 in the CNS resulted in decreased interleukin-12 receptor expression by antigen-specific T cells. Collectively, these results indicate that sustained, tissue-specific expression of CCL2 in vivo down-regulates the Th1 autoimmune response, culminating in milder clinical disease.

Animals↗
PubMed2005

CCL2 and CXCL1 trigger calcitonin gene-related peptide release by exciting primary nociceptive neurons.

Chemokines are important mediators in immune responses and inflammatory processes. Calcitonin gene-related peptide (CGRP) is produced in dorsal root ganglion (DRG) neurons. In this study, CGRP radioimmunoassay was used to investigate whether the chemokines CCL2 and CXCL1 could trigger CGRP release from cultured DRG neurons of neonatal rats and, if so, which cellular signaling pathway was involved. The results showed that CCL2 and CXCL1 ( approximately 5-100 ng/ml) evoked CGRP release and intracellular calcium elevation in a pertussis toxin (PTX)-sensitive manner. The CGRP release by CCL2 and CXCL1 was significantly inhibited by EGTA, omega-conotoxin GVIA (an N-type calcium channel blocker), thapsigargin, and ryanodine. Pretreatment of DRG neurons for 30 min with the inhibitors of phospholipase C (PLC) and protein kinase C (PKC) but not mitogen-activated protein kinases (MAPKs) significantly reduced CCL2- or CXCL1-induced CGRP release and intracellular calcium elevation. Intraplantar injection of CCL2 or CXCL1 produced hyperalgesia to thermal and mechanical stimulation in rats. These data suggest that CCL2 and CXCL1 can stimulate CGRP release and intracellular calcium elevation in DRG neurons. PLC-, PKC-, and calcium-induced calcium release from ryanodine-sensitive calcium stores signaling pathways are involved in CCL2- and CXCL1-induced CGRP release from primary nociceptive neurons, in which chemokines produce painful effects via direct actions on chemokine receptors expressed by nociceptive neurons.

Analysis of Variance↗
PubMed2026

Nucleolin promotes neuropathic pain by increasing chromatin accessibility at the Ccl2 promoter in primary sensory neurons.

Nerve injury-induced transcriptional alterations in primary sensory neurons of the dorsal root ganglion (DRG) constitute a key molecular basis for the development of neuropathic pain. Nucleolin (NCL), a highly conserved multifunctional nucleolar protein, regulates gene transcription. Here, we identify that NCL is expressed exclusively in the nuclei of DRG neurons. Peripheral nerve injury time-dependently upregulates Ncl mRNA and NCL protein levels in injured DRG neurons. Blocking this upregulation through DRG microinjection of the adeno-associated virus 9 (AAV9) expressing an shRNA targeting Ncl attenuates nerve injury-induced increases of C-C motif chemokine ligand 2 (CCL2) mRNA and its protein in injured DRG and alleviates the development and maintenance of mechanical, heat and cold hypersensitivities. Conversely, mimicking DRG NCL upregulation through DRG microinjection of AAV9 carrying the full-length Ncl coding sequence increases Ccl2 mRNA and CCL2 protein levels in microinjected DRGs and produces neuropathic pain-like symptoms in the absence of nerve injury. Mechanistically, peripheral nerve injury increases NCL occupancy at the Ccl2 promoter and enhances chromatin accessibility at this locus, resulting in elevated CCL2 expression in injured DRG neurons, which is reversed by NCL knockdown. Given that Ncl mRNA is co-expressed with Ccl2 mRNA in individual DRG neurons, our findings suggest that NCL upregulation in the DRG contributes to neuropathic pain likely by increasing chromatin accessibility at the Ccl2 promoter in primary sensory neurons.

Animals↗
PubMed2006

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. Astrocytes were the predominant source of CCL2 and CCL3 in the striatum and the substantia nigra, and dopaminergic neurons in the substantia nigra constitutively expressed these two chemokines. MPTP treatment resulted in decreased CCL2 expression and increased CCL3 expression in the surviving dopaminergic neurons. Because we found that CCL2 induced production of TNF-alpha in microglial cells, a cytokine known to play a detrimental role in PD, we anticipated that deletion of the genes encoding CCL2 and CCR2, its major receptor, would confer a protective phenotype. However, MPTP-induced striatal dopamine depletion was comparable in double knockout and wild-type mice. Our results demonstrate that chemokines such as CCL2 are induced following MPTP treatment, but that at least within the context of this PD model, the absence of CCL2 and CCR2 does not protect against striatal dopamine loss.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2005

The Toxoplasma surface protein SAG1 triggers efficient in vitro secretion of chemokine ligand 2 (CCL2) from human fibroblasts.

Chemokines play an important role in the physiopathology of toxoplasmosis in murine models. Infection of different human cell types by Toxoplasma gondii induces the secretion of these immune mediators. The aim of our study was to identify parasite molecules that could be involved in the triggering of chemokine ligand 2 (CCL2) secretion during T. gondii host cell invasion: surface, micronemal, rhoptry and dense granule proteins. The secretion of CCL2 was studied 1) after infection of human fibroblasts with mutants of Toxoplasma RH strain deficient either for GRA5, GRA2-GRA6, ROP1 or SAG1; 2) after stimulation by micronemal proteins or by the immunodominant surface antigen 1 of T. gondii. CCL2 secretion was quantified by ELISA at 3 h and/or 24 h after infection or stimulation. Infection by Deltagra2-Deltagra6, Deltagra5 or Deltarop1 mutants did not modify the level of CCL2, as compared with the level measured after infection with the wild-type strain. Moreover, stimulation with micronemal proteins did not increase the secretion of this chemokine. By contrast, the level of CCL2 was increased 3 h post-stimulation by purified or recombinant SAG1. Specificity of this effect was confirmed by the decrease in CCL2 secretion when human fibroblasts were infected with the Deltasag1 mutant (48%) as compared with the wild-type strain (100%). In conclusion, this major Toxoplasma surface protein SAG1, specific to the tachyzoite stage, is directly or indirectly involved in the cellular mechanisms triggering CCL2 secretion after T. gondii infection. These results could explain the parasitic mechanisms leading to cell infiltrates detected only in the presence of tachyzoites, a phenomenon observed in toxoplasmic reactivation.

Animals↗
PubMed2005

CCR2 expression by brain microvascular endothelial cells is critical for macrophage transendothelial migration in response to CCL2.

While the expression of chemokine receptors by endothelial cells is now well established, little is known of the function of these receptors at this cellular locale. However, given that chemokines are instrumental in directing leukocytes to specific parenchymal sites, one possibility is that endothelial chemokine receptors play a role in the process of leukocyte extravasation. To test this hypothesis, we investigated the contribution of CCR2, the major cognate receptor for the chemokine CCL2 (formerly known as MCP-1), to CCL2-stimulated transendothelial migration of macrophages (mØ) across cultured brain microvascular endothelial cells (BMEC). Specifically, we prepared both BMEC and mØ from wild-type (WT) mice and mice deficient in CCR2; i.e., CCR2 (-/-), and compared the ability of WT and CCR2 (-/-) BMEC to support CCL2-stimulated transendothelial migration of WT and CCR2 (-/-) mØ. In response to CCL2, WT mØ, but not CCR2 (-/-) mØ, were stimulated to migrate across WT BMEC, consistent with the recognized obligatory role for CCR2 in mediating CCL2-stimulated responses. Remarkably, however, neither WT nor CCR2 (-/-) mØ were stimulated by CCL2 to migrate across CCR2 (-/-) BMEC. In contrast, both types of mØ were able to migrate similarly across both types of BMEC in response to another chemokine--CCL3 (formerly known as MIP-1alpha)--which utilizes receptors other than CCR2. Lastly, CCL2-induced mØ transendothelial migration was blocked by treatment of WT BMEC with pertussis toxin, suggesting that CCR2 is functionally coupled to the inhibitory G protein Galphai, much as it is in other cell types. These results highlight a heretofore-unrecognized role for endothelial CCR2 in mediating transendothelial migration.

Animals↗
PubMed2001

Chemokines CXCL10 and CCL2: differential involvement in intrathecal inflammation in multiple sclerosis.

Studies of chemokines in cerebrospinal fluid (CSF) of patients with active multiple sclerosis (MS) have indicated that specific chemokines may have important roles in disease pathogenesis. We previously reported that CSF concentrations of CXCL10 (previously known as IP-10) were elevated in MS patients in relapse, whilst levels of CCL2 (MCP-1) were reduced. Here, we report a serial analysis of CSF CXCL10 and CCL2 concentrations in 22 patients with attacks of MS or acute optic neuritis (ON) treated with methylprednisolone, and 26 patients treated with placebo in two randomized controlled trials. Chemokine concentrations were measured by enzyme linked immunosorbent assay (ELISA) in CSF obtained at baseline and after 3 weeks, and were compared with other measures of intrathecal inflammation. At baseline CSF concentrations of CCL2 were significantly lower in the patient group than in controls. The levels of CXCL10 were higher in the patient group than in controls but two outliers in the control group also had high CSF concentrations of CXCL10. The CSF concentrations of CXCL10 did not change over time or after treatment. The CSF concentration of CXCL10 was positively correlated with the CSF leukocyte count, the CSF concentration of neopterin, matrix metalloproteinase (MMP)-9, and intrathecal IgG and IgM synthesis. The concentration of CCL2 increased between baseline for 3 weeks in both groups, more distinctly so in patients treated with methylprednisolone. CCL2 correlated negatively with MMP-9 and IgG synthesis levels. CXCL10 may be involved in the maintenance of intrathecal inflammation whereas CCL2 correlates negatively with measures of inflammation, suggesting differential involvement of CXCL10 and CCL2 in CNS inflammation.

Anti-Inflammatory Agents↗
PubMed2006

Protein kinase Calpha-RhoA cross-talk in CCL2-induced alterations in brain endothelial permeability.

Monocyte chemoattractant protein-1 (MCP-1 or CCL2) regulates blood-brain barrier permeability by inducing morphological and biochemical alterations in the tight junction (TJ) complex between brain endothelial cells. The present study used cultured brain endothelial cells to examine the signaling networks involved in the redistribution of TJ proteins (occludin, ZO-1, ZO-2, claudin-5) by CCL2. The CCL2-induced alterations in the brain endothelial barrier were associated with de novo Ser/Thr phosphorylation of occludin, ZO-1, ZO-2, and claudin-5. The phosphorylated TJ proteins were redistributed/localized in Triton X-100-soluble as well as Triton X-100-insoluble cell fractions. Two protein kinase C (PKC) isoforms, PKCalpha and PKCzeta, had a significant impact on this event. Inhibition of their activity using dominant negative mutants PKCalpha-DN and PKCzeta-DN diminished CCL2 effects on brain endothelial permeability. Previous data indicate that Rho/Rho kinase signaling is involved in CCL2 regulation of brain endothelial permeability. The interactions between the PKC and Rho/Rho kinase pathways were therefore examined. Rho, PKCalpha, and PKCzeta activities were knocked down using dominant negative mutants (T17Rho, PKCalpha-DN, and PKCzeta-DN, respectively). PKCalpha and Rho, but not PKCzeta and Rho, interacted at the level of Rho, with PKCalpha being a downstream target for Rho. Double transfection experiments using dominant negative mutants confirmed that this interaction is critical for CCL2-induced redistribution of TJ proteins. Collectively these data suggest for the first time that CCL2 induces brain endothelial hyperpermeability via Rho/PKCalpha signal pathway interactions.

Animals↗
PubMed2003

CCL2 transgene expression in the central nervous system directs diffuse infiltration of CD45(high)CD11b(+) monocytes and enhanced Theiler's murine encephalomyelitis virus-induced demyelinating disease.

CCL2 is a member of the CC chemokine family that mediates the migration and recruitment of monocytes and T cells and has been identified in the central nervous system (CNS) during several neuroinflammatory diseases. In order to examine the biological effect of constitutive CCL2 expression in the CNS, the authors engineered a mouse that expressed CCL2 in the CNS under control of the human glial fibrillary acidic protein (hGFAP) promoter. The results demonstrated that transgenic expression of CCL2 in the CNS resulted in diffuse CNS monocyte infiltration and accumulation. Transgenic CCL2 expression did not alter normal development, differentiation, or function of T cells. There was no evidence of overt CNS disease or other pathologic phenotype when mice were left unchallenged with antigen or uninfected. However, when CCL2 transgenic mice were given a peripheral challenge of lipopolysaccharide (LPS), an inflammatory infiltrate with organized perivascular lesions developed. Infection of the transgenic mice with Theiler's murine encephalomyelitis virus (TMEV) resulted in accelerated onset and increased severity of clinical and histological disease. These results suggest that CCL2 expression in the CNS is a major pathogenic factor that drives macrophage accumulation in the development of CNS inflammatory disease.

Animals↗
PubMed2004

Natural killer T cells infiltrate neuroblastomas expressing the chemokine CCL2.

CD1d-restricted Valpha24-Jalpha18-invariant natural killer T cells (iNKTs) are potentially important in tumor immunity. However, little is known about their localization to tumors. We analyzed 98 untreated primary neuroblastomas from patients with metastatic disease (stage 4) for tumor-infiltrating iNKTs using TaqMan((R)) reverse transcription polymerase chain reaction and immunofluorescent microscopy. 52 tumors (53%) contained iNKTs, and oligonucleotide microarray analysis of the iNKT(+) and iNKT(-) tumors revealed that the former expressed higher levels of CCL2/MCP-1, CXCL12/SDF-1, CCL5/RANTES, and CCL21/SLC. Eight tested neuroblastoma cell lines secreted a range of CCL2 (0-21.6 ng/ml), little CXCL12 (</=0.1 ng/ml), and no detectable CCL5 or CCL21. CCR2, the receptor for CCL2, was more frequently expressed by iNKT compared with natural killer and T cells from blood (P < 0.001). Supernatants of neuroblastoma cell lines that produced CCL2 induced in vitro migration of iNKTs from blood of patients and normal adults; this was abrogated by an anti-CCL2 monoclonal antibody. CCL2 expression by tumors was found to inversely correlate with MYCN proto-oncogene amplification and expression (r = 0.5, P < 0.001), and MYCN-high/CCL2-low expression accurately predicted the absence of iNKTs (P < 0.001). In summary, iNKTs migrate toward neuroblastoma cells in a CCL2-dependent manner, preferentially infiltrating MYCN nonamplified tumors that express CCL2.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2006

Association between increased CCL2 (MCP-1) expression in lesions and persistence of disease activity in giant-cell arteritis.

OBJECTIVE: Patients with giant-cell arteritis (GCA) usually respond dramatically to corticosteroid treatment. However, recurrences are frequent and corticosteroid requirements are highly variable among patients. The aim of our study was to identify genes potentially involved in disease persistence. METHODS: Gene expression was explored with cDNA arrays in temporal artery biopsies from six GCA patients with relapsing disease and six patients who easily achieved sustained remission. Differentially expressed genes of interest were subsequently analysed by quantitative real-time polymerase chain reaction (PCR) and immunohistochemistry in temporal artery biopsies from 35 patients with biopsy-proven GCA and nine controls. RESULTS: CCL2 (MCP-1) was up-regulated in temporal artery samples from relapsing individuals. In the extended series of patients, CCL2 mRNA concentration in lesions was significantly higher than in controls (31 +/- 15.6 vs 0.44 +/- 0.10, P = 0.0001). In addition, CCL2 was more abundant in patients who experienced two or more relapses during the first year compared with those who endured sustained remission (127 +/- 82 vs 11 +/- 5.5, P = 0.0233) and correlated with the cumulated prednisolone dose (R = 0.533, P = 0.0024). CCL2 mRNA concentration correlated with IL-1beta (R = 0.45, P = 0.02), tumour necrosis factor-alpha (TNF-alpha) (R = 0.47, P = 0.013) and IL-6 (R = 0.52, P = 0.0053) mRNA. However, circulating CCL2 determined by ELISA was decreased in patients with strong systemic inflammatory response, suggesting that reduction in circulating CCL2 may reinforce the local gradient in lesions. CONCLUSION: Increased CCL2 (MCP-1) expression in lesions is associated with persistence of disease activity in GCA.

Anti-Inflammatory Agents↗
PubMed2005

The chemokine CCL2 is required for control of murine gastric Salmonella enterica infection.

Salmonella enterica is a gram-negative intracellular pathogen that can cause a variety of diseases ranging from gastroenteritis to typhoid fever. The Typhimurium serotype causes gastroenteritis in humans; however, infection of mice results in an enteric fever that resembles human typhoid fever and has been used as a model for typhoid fever. The present study examined the role of the chemokine CCL2 in the control of Salmonella infection. Upon infection with salmonellae, mucosal expression of CCL2 is rapidly up-regulated, followed by systemic expression in the spleen. CCL2(-/-) mice became moribund earlier and had a higher rate of mortality compared to wild-type C57BL/6 mice. Moreover, CCL2(-/-) mice had significantly higher levels of bacteria in the liver compared to wild-type controls. Mucosal and serum interleukin-6 and tumor necrosis factor alpha levels were elevated in CCL2(-/-) mice compared to wild-type mice. In vitro analysis demonstrated that CCL2(-/-) macrophages infected with salmonellae resulted in dysregulated cytokine production compared to macrophages derived from wild-type mice. These data are the first to directly demonstrate CCL2 as a critical factor for immune responses and survival following S. enterica infection.

Animals↗
PubMed2003

Post-BMT lung injury occurs independently of the expression of CCL2 or its receptor, CCR2, on host cells.

Idiopathic pneumonia syndrome (IPS) is a significant cause of mortality post-bone marrow transplant (BMT) in humans. In our murine model, lethal pre-BMT conditioning and allogeneic T cells result in the recruitment of host antigen-presenting cells (APC) and donor T cells into the lung post-BMT concomitant with development of severe lung dysfunction. CCL2 induction is found in bronchoalveolar lavage fluid (BALF) before host monocyte influx. The major receptor for CCL2 is CCR2 present on monocytes; this interaction can play a crucial role in monocyte recruitment in inflammation. To determine whether blockade of the CCL2/CCR2 pathway could hinder host monocyte influx, lethally conditioned wild-type (WT), CCL2(-/-), or CCR2(-/-) mice were transplanted with allogeneic marrow and spleen cells. WT and (-/-) recipients exhibited equivalent lung dysfunction post-BMT. The frequencies of host macrophages as well as donor CD4(+) and CD8(+) T cells in lungs post-BMT did not differ between WT and (-/-) recipients. However, the T cell dependency of the host CD11b(+) major histocompatibility complex class II(+) cell influx was lost in CCR2(-/-) recipients. In CCR2(-/-) mice, this influx was accompanied by elevated levels of CCL20. Post-BMT BALF and sera of (-/-) mice did not reveal any decrease in cytokines or chemokines compared with WT mice. CCL2(-/-) mice had a deficiency of CCL2 in their BALF and sera post-BMT, confirming our hypothesis that CCL2 is predominantly host derived. Therefore, IPS can occur independently of host expression of CCL2 or CCR2, and compensatory mechanisms exist for regulating APC recruitment into the lung during the early post-BMT period.

Animals↗
PubMed2003

Endogenous CCL2 (monocyte chemotactic protein-1) modulates human immunodeficiency virus type-1 replication and affects cytoskeleton organization in human monocyte-derived macrophages.

CC chemokine ligand 2 (CCL2) is constitutively expressed at high levels in human peripheral blood monocytes, and its expression is further up-modulated during their differentiation into macrophages as well as in the course of HIV infection. To investigate the role of endogenous CCL2 on HIV replication and macrophage function, CCL2's activity was neutralized by specific antibodies. Infection of monocyte-derived macrophages with laboratory-adapted HIV-1 or primary viral isolates in the continuous presence of anti-CCL2 antibody resulted in significantly lower p24 Gag antigen release with respect to control cultures. Interestingly, CCL2 neutralization did not affect the early steps of the HIV life cycle but resulted in the intracellular accumulation of p24 Gag antigen. Simultaneously, remarkable changes in cell morphology and size occurred in cell cultures maintained in the presence of anti-CCL2 antibody. These results suggest that CCL2 may represent an autocrine factor important for enhancing virion production likely by affecting the macrophage cytoskeleton.

Autocrine Communication↗