CCR2

CCR2 (C-C motif chemokine receptor 2) is a key regulator of immune cell migration, particularly monocytes, playing a crucial role in inflammation, fibrosis, and tumor progression. 

By interacting with its primary ligand, CCL2, CCR2 contributes to disease processes in liver disorders, cancer, atherosclerosis, and neuroinflammation, making it a potential therapeutic target for conditions driven by chronic inflammation and immune cell recruitment.

What is CCR2?

CCR2 (C-C motif chemokine receptor 2) is a chemotactic receptor involved in immune cell migration, primarily by recruiting immune cells to areas of inflammation, tissue injury, and active fibrosis. 

CCR2 is found on monocytes, B and T cells, and immature dendritic cells, although it primarily attracts circulating monocytes. It is also found on some brain cells.

CCR2 binds to CCL2 (C-C motif chemokine ligand 2), also known as Monocyte Chemoattractant Protein-1 (MCP-1), a chemokine that signals specific immune system actions.

In addition to CCL2 (the strongest CCR2 activator), it is also activated by chemokines, including CCL7, and CCL8, which trigger signaling pathways that promote the recruitment of monocytes and other immune cells to affected tissues. 

CCR2’s activation leads to processes such as cell migration, survival, and tissue infiltration, which are key in inflammation, fibrosis, and tumor progression. It is especially implicated in liver diseases, chronic inflammation, and certain cancer types, where its blockade has shown potential in reducing disease progression. 

Furthermore, CCR2's role in leukocyte homeostasis highlights its importance not only in active inflammation but also in resolving inflammation and restoring immune balance.

CCR2’s Role in Various Diseases

CCR2 plays a role in various disease processes: 

Liver Diseases

CCR2 is a major player in liver pathologies, including nonalcoholic steatohepatitis (NASH), alcoholic liver disease, and hepatocellular carcinoma (HCC). 

It facilitates the recruitment of monocytes to liver tissue, where they contribute to inflammation, fibrosis, and tumor progression. The CCL2/CCR2 axis, in particular, drives fibrosis and supports cancer cell migration in HCC. 

Therapeutically, CCR2 antagonists like cenicriviroc have shown promise in treating liver fibrosis and reducing inflammation in NASH and alcoholic liver disease.

Tumor Progression and Cancer

CCR2 plays a key role in cancer progression by mediating the recruitment of immune cells, such as monocytes and macrophages, to tumor sites through its ligand CCL2. This recruitment supports tumor growth, metastasis, and immune suppression. 

Elevated CCR2 and CCL2 levels are linked to increased tumor aggressiveness and poor prognosis in cancers like prostate, breast, ovarian, and hepatocellular carcinoma (HCC). 

In HCC, CCR2 recruits tumor-associated macrophages (TAMs), which promote tumor progression by secreting proinflammatory cytokines, and angiogenic factors and suppressing T-cell responses. 

Targeting CCR2 has the potential to mitigate tumor progression, at least in HCC, by modulating macrophage activity. It may also inform prognosis in lung adenocarcinoma.

Inflammatory Diseases

CCR2 plays a central role in the recruitment of inflammatory monocytes in conditions like multiple sclerosis (MS), Alzheimer's disease, and ischemic stroke. These monocytes can exacerbate inflammation and tissue damage, but they may also have protective effects. 

The therapeutic inhibition of CCR2 has been explored in models of MS and ischemic stroke to reduce disease severity, although its dual role in inflammation complicates treatment strategies.

Central Nervous System (CNS) Inflammation

In CNS diseases, CCR2 facilitates the migration of monocytes to sites of injury, where they can differentiate into macrophages or microglia. While these cells contribute to neuroinflammation, their accumulation may also promote tissue repair, indicating a dual role in brain pathology. 

In diseases like Alzheimer's, CCR2-dependent monocytes may play a protective role by clearing amyloid plaques, but their involvement can also drive disease progression in some cases.

Pulmonary Diseases

In malaria-associated acute respiratory distress syndrome (MA-ARDS), CCR2 is essential for the resolution of inflammation and the restoration of leukocyte homeostasis in the lungs. 

While it is not required for disease resolution, CCR2 is critical for the re-entry of eosinophils and interstitial macrophages, which are necessary for balancing immune responses during recovery.

Atherosclerosis

The CCL2–CCR2 axis plays an important role in atherosclerosis by helping monocytes move to areas of inflammation in the arteries, which contributes to plaque formation and instability. 

Studies in animals and research reviews have shown that blocking CCL2 or its receptor CCR2 can reduce the size of plaques and make them more stable by limiting the number of macrophages, suggesting that targeting this pathway could help treat heart disease. 

In humans, higher levels of CCL2 in plaques are linked to more unstable plaques and a higher risk of conditions like stroke and coronary artery disease. 

Rheumatoid Arthritis (RA)

CCR2 is a chemokine receptor necessary for the migration of immune cells, particularly monocytes, into inflamed tissues. In RA, its ligand CCL2 is elevated in the synovium, contributing to chronic inflammation and joint damage by promoting immune cell recruitment, osteoclastogenesis, angiogenesis, and effector T cell migration.

While CCR2 blockade has shown promise in animal models by reducing synovial inflammation, clinical trials in RA patients have had mixed results. CCR2 inhibition can decrease receptor expression on immune cells, but it has not consistently improved inflammation or clinical symptoms. 

This indicates that targeting CCR2 alone may not be sufficient for effective RA treatment, highlighting the need for further research into combination therapies.

CCR2: Therapeutic Potential and Challenges

CCR2 antagonists have therapeutic potential in treating chronic inflammation, fibrosis, and certain cancers. However, targeting CCR2 must be done cautiously, as blocking its function can impair beneficial immune responses, such as tissue repair and immune surveillance. 

Studies on CCR2 inhibitors, like INCB3344 and MK-0812, have shown mixed results in clinical trials, underscoring the need for further research into balancing its effects in different disease contexts.

Test Procedure and Interpretation

CCR2 is not a routinely tested biomarker. Clinicians may order CCR2 expression testing in specific cases, particularly for research purposes or in clinical trials investigating immune responses in diseases such as rheumatoid arthritis, atherosclerosis, and certain cancers.

Testing Procedure and Preparation Requirements

CCR2 expression is often assessed using flow cytometry or immunohistochemistry or, occasionally, using a targeted positron emission tomography (PET) radiotracer called 64Cu-DOTA-ECL1i. 

Flow cytometry and immunohistochemistry tests require blood or tissue samples, and specific sample handling procedures should be followed to preserve cell integrity and receptor activity. 

No special preparation is generally needed for flow cytometry, but sample collection conditions (e.g., anticoagulated blood) should be carefully considered.

CCR2 PET imaging is used for non-invasive monitoring of abdominal aortic aneurysm progression and rupture risk; this may require special preparation, which should be confirmed with the ordering physician.

Always consult with the ordering provider or lab company to confirm testing preparation.

Normal Reference Ranges

There are no universally established normal reference ranges for CCR2 expression because values can vary based on patient demographics and the conditions under study. Reference values are typically derived from research studies and may vary depending on the testing methodology used.

Clinical Implications of Elevated Levels

Increased CCR2 expression indicates a heightened response to CCL2, promoting enhanced immune cell recruitment and activation. 

This may suggest an active inflammatory process, such as in rheumatoid arthritis, atherosclerosis, or certain cancer types. Elevated CCR2 levels are often observed in the recruitment of inflammatory cells to affected tissues. 

In cancer, increased CCR2 expression on tumor-associated macrophages can contribute to tumor growth and metastasis.

Clinical Implications of Decreased Levels

Low CCR2 expression may indicate reduced responsiveness to CCL2, potentially impairing immune cell trafficking to sites of infection or inflammation. This may be relevant in conditions where immune responses are impaired. 

Research also suggests that therapies targeting CCR2 may be less effective in patients with low CCR2 expression, highlighting the potential significance of this finding in therapeutic contexts.