Which cells express ccr2

These three papers suggest an interplay between CCL2 and monocytes that leads to decreased tumor cell growth. More evidence shows that CCL2 mediates tumor cell killing indirectly by activating macrophages. Moreover, CCL2 treatment induced transcription and phosphorylation of the transcription factor c-Jun Furthermore, the authors could show that CCL2 treatment led to a drastic change in actin redistribution, bundling, and aggregation, which is a typical response of leukocytes to chemokines [as reviewed in ] and could also be blocked by PD The effect could be inhibited by PD in a dose-dependent manner.

Cytotoxicity of macrophages is modulated via CCL2 by increasing the level of membrane-bound FasL, a protein involved in apoptosis, which renders CCL2-primed macrophages more cytotoxic. A series of publications suggest that CCL2 can also synergize with bacterial endotoxins to activate macrophages to become tumoricidal. Subsequent coculturing of these macrophages with CT26 cells showed that macrophage cytotoxicity assessed by [3H]-thymidine release from lysed cells toward CT26 tumor cells was increased in a CCL2-dependent manner, as the addition of CCL2 strongly increased cytotoxicity and the addition of anti-CCL2 antibody reduced cytotoxicity.

The findings were confirmed in vivo , where CCL2-positive tumor cells produced significantly fewer lung metastases In addition, when using the bacterial products lipopeptide and muramyl tripeptide phosphatidylethanolamine to activate PEMs in vitro , the effect on cytotoxicity was very similar Singh et al.

Owing to the fact that, in their assays, the sequence of the stimuli was important first chemokine stimulation, then LPS stimulation , the authors suggested that CCL2 can prime macrophages to respond to a subsequent signal, which corresponds well with CCL2's ability to prime myeloid cells described in CCL2 Primes Cells to Respond to Subsequent Infection of this review Similar findings were also obtained in an in vivo model, where tumor cells producing high levels of CCL2 transfected with CCL2 complementary DNA and antibiotic selection before injection were significantly lysed by macrophages of mice treated with LPS, whereas parental or control transfected cells were not Moreover, alveolar macrophages were isolated after injection of CCL2-transfected fibroblasts or mock-transfected fibroblasts into the tail vein.

Cytotoxicity of these macrophages was then tested in vitro by coculture with radiolabeled RENCA cells. This finding was backed up in a murine in vivo model of experimental lung metastases, where subcutaneous administration of CCL2-transfected fibroblasts along with RENCA cells and subsequent administration of transfected fibroblasts at days 3, 5, and 7 into the original site of injection reduced tumor size and amount of metastasis to the lung In all the studies of this paragraph, CCL2 secreted from different cell types, being tumor cells and fibroblasts is involved in priming macrophages to respond to LPS.

Apart from monocytes and macrophages, also neutrophils have been investigated in the context of influencing tumor progression in the presence of CCL2.

A potential antimetastatic effect of CCL2 via activation of neutrophils has been described. The effect was also shown for naive murine neutrophils on the 4T1 cancer cell line. The cytotoxic effect was underlined by increased H 2 O 2 production in neutrophils after exogenous CCL2 was added to the media. In vivo , knockout of CCL2 in primary tumors of mice injected intradermally with BF10 melanoma and LLC cells lung carcinoma inhibited this neutrophil activation in tumor-bearing mice, and CCL2 knockout tumors showed earlier metastasis in vivo.

Together, these results indicated that CCL2 released from the primary tumor may have an antimetastatic effect by activation of neutrophils In contrast, Lavender et al. Tumor-entrained neutrophils, i. However, the situation was different for the less aggressive 67NR cell line. Naive neutrophils were not active against the 67NR cell line in cocultures, and the addition of exogenous CCL2 did not change that. However, when CCL2 pretreated tumor-naive neutrophils were seeded together with 67NR cells, the neutrophils were then cytotoxic.

On the other hand, tumor-entrained neutrophils gained activity against 67NR cells when exogenous CCL2 was added to the coculture. To add to the complexity of the situation, when testing the hypothesis in vivo , exogenous CCL2 had an opposite effect on tumors, as it led to increased tumor localization of 67NR cells in mice intravenously injected with 67NR cells and intranasal delivery of CCL2 The findings of the two above studies show that, under certain circumstances, CCL2 is able to confer antitumorigenic and antimetastatic characteristics to neutrophils.

However, the exact context of these actions needs to be defined before a definite conclusion can be made. In summary, direct effect on monocytes, macrophages, and neutrophils growth inhibitory and tumoricidal as well as synergistic effects of CCL2 with bacterial endotoxins on activated macrophages were described.

These findings characterizing CCL2's effect on reducing tumor cell growth and increased killing via influencing myeloid cells suggest an antitumoricidal role of CCL2. However, these findings are in direct contrast with the publications showing that CCL2 favors tumor progression via M2-macrophage polarization see CCL2 Enhances Host Defense, Cellular Cleanup, and Allergic Responses and immunosuppression see CCL2 Can Confer Immunosuppressive Effects on T Cells via Myeloid Cells , enhances tumor cell survival and proliferation 8 , 74 and metastasis 77 and that high CCL2 correlates with an unfavorable prognosis in several types of cancer such as breast cancer , , lung adenocarcinoma , or pancreatic cancer Moreover, most tumor cell lines produce CCL2 and are able to grow in vivo in wild-type as well as CCL2 knockout mice , These contrasting effects call for a more detailed investigation in single cancer types, as they might be accountable for the failures in therapeutically targeting CCL2 see Discussion and Conclusions.

Potential explanations for the varying effects of CCL2 can be found when studying the molecular aspects of CCL2 biology. This topic is beyond the scope of the review, but the authors would like to point out several potentially important aspects in the following paragraph. When analyzing the experimental setups see Table 5 for details , it is of interest to note that the source of CCL2 might have an influence on the functional outcome of CCL2 signaling.

For example, nitration of its tyrosine residues by reactive nitrogen species, such as peroxynitrite, has been shown to reduce CCL2-mediated monocyte migration in diffusion gradient chemotaxis and transendothelial migration in Transwell assays , Finally, various glycosylated forms of human CCL2 from PBMCs have been characterized, which showed less chemoattractant activity on monocytes For example, Brault et al.

The observed effect might be due to different PTMs or to the potential presence of additional stimulatory or inhibitory factors in the supernatant. Moreover, Yoshimura et al. Murine CCL2 has a glycosylated 50 amino-acid-long C-terminal tail, which can be cleaved by the protease plasmin generating a chemotactically more potent truncation variant, whereas the N-terminus is more conserved , Moreover, CCL2 is capable of oligomerizing.

Proudfoot et al. In contrast Paolini et al. To add to the complexity, CCL2 can also form heterooligomers with other chemokines On top of that, the active oligomerization state might be different for human and mouse CCL2 as they differ in their C-terminal tail and is influenced by their interaction with glycosaminoglycans Apart from the molecular aspects of CCL2 biology, the tumor microenvironment is highly complex, and a multitude of molecules and cell types impact on the tumor vs.

CCL2 is certainly not the only culprit, but it is definitely present in the tumor microenvironment and has the potential to impact not only on cancer or stromal cells but also on myeloid cells. T cells are also crucial players in host defense in the form of adaptive immune responses, which are tightly interwoven with myeloid-cell-driven innate immunity.

The suppressive effect was accompanied by lowered expression of costimulatory molecules such as HLA-DR and increased expression of immunosuppressive molecules such as PD-L1. Expression of Rgs2, an inhibitor of cell proliferation and mediator of cell differentiation , was shown to be highly upregulated in MDSCs from tumor-bearing mice, and knockout of Rgs2 led to decreased CCL2 expression and reduced tumor growth due to decreased vascularization in vivo.

Taken together, these findings show that CCL2 is involved in conveying immunosuppressive properties on T cells via myeloid cells. Therefore, tumors can take advantage of CCL2 secretion by hampering immune defense and increasing angiogenesis at the same time. CCL2 was one of the first chemokines described and has since been extensively studied for its chemoattractant function 37 , , Multiple effects of CCL2 are owed to the types of cells it recruits. However, increasing evidence has shown that CCL2 may be far more than merely a guidance cue for leukocytes.

In this review, we have summarized how this chemokine influences myeloid cell function and therefore modulates immune responses Figure 1. Among other effects, CCL2 has been shown to enhance the cell-killing properties of monocytes and macrophages, to enhance survival of macrophages and neutrophils, and to have profound influence on macrophage polarization and corresponding effector molecule secretion.

The summarized data of CCL2's effects show that downstream signaling cascades of CCL2 are not unique to cell migration and often elicit multiple different functions.

For example, ERK1, ERK2, and p38 have been shown to be involved in processes as diverse as macrophage activation, tumor cytotoxicity, polarization, and lipid body formation , , All in all, CCL2 is not a maverick.

A discussion about CXCL10 and CCL1 as checkpoints was recently published , as information about these chemokines in this new role is accumulating. However, the research field about chemokines as checkpoints is growing, and potentially, more findings about CCL2 can be anticipated.

Targeting CCL2 signaling is of high clinical interest due to its involvement in various types of cancer, as well as other difficult to treat diseases, such as atherosclerosis 63 , multiple sclerosis 64 , and diabetes Numerous clinical trials www. Despite the efforts, many small molecule CCR2 antagonist programs have ended in discontinuation for various reasons, such as lack of efficacy or company strategy, whereas some CCR2 antagonists are still in development for instance by Chemocentrix e.

The lack of success in targeting CCL2 has been mirrored with approaches that interfere with the bioactivity of several chemokines in different diseases [reviewed in ], which have also so far not lived up to early expectations.

However, some evidence suggests that the chemokine redundancy that is evident in vitro does not occur, at least to the same extent, in vivo Other authors argue that inappropriate target selection and ineffective dosing may be more likely mistakes made on the way to CCR targeting therapies Moreover, targeting chemokines and their receptors affects physiological cell migration and development and is therefore a double-edged sword This hurdle could be overcome by making use of novel targeting platforms, such as bispecifics, or applying combination therapies with checkpoint inhibitors At present, our molecular understanding of chemokine presentation, structure—function relationships of chemokines and their co- receptors, differential signaling of ligands, and feedback loops regulating the chemokine signaling network is still incomplete and make it currently challenging to interpret or predict the consequences of modulating chemokine behavior in vivo , This review has shown that it has to be taken into consideration that CCL2 has a significant impact on immune cells that goes beyond attraction.

Correspondingly, it has recently been shown that the efficiency of trastuzumab relies on CCL2 levels and monocytes present in the TME in mammary carcinoma in vivo A higher CCL2 level also increased the response to chemotherapy paclitaxel and cisplatin Concluding, we have summarized how multifaceted the effects of CCL2 on myeloid cells are. The outcome of the response is highly context, cell type, and time dependent, and in the case of polarization, it can go in different directions.

Justifiably, in a lot of previous publications about CCL2, the focus has been put on monocyte infiltration, which is the chemokine's best studied function and a prerequisite for impacting on myeloid cells subsequently. With this review, we would like to suggest also taking into account the potential impact of CCL2 on myeloid cell function, as CCL2 might be involved in several subsequent steps of the pathway, including polarization, activation, and survival of myeloid cells.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Baggiolini M. Chemokines and leukocyte traffic.

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