CCL4

CCL4, also known as macrophage inflammatory protein-1β (MIP-1β), is a chemokine that plays a key role in immune cell recruitment, inflammation, and disease progression. 

Through its interaction with the CCR5 receptor, CCL4 influences immune responses in conditions such as autoimmune diseases, cardiovascular disease, cancer, and HIV, making it a potential biomarker and therapeutic target for various inflammatory and immune-related disorders.

What is CCL4?

CCL4, also known as macrophage inflammatory protein-1β (MIP-1β), is a chemokine important in immune responses and inflammation. CCL4 is produced by various immune cells, including macrophages, neutrophils, fibroblasts and endothelial epithelial cells, dendritic cells, and lymphocytes. 

CCL4 has a specific receptor, CCR5, and acts as a chemoattractant for some immune cells including natural killer cells and monocytes.

CCL4’s Role In The Immune System

CCL4 has important roles in the immune system:

Chemokine Functions

It regulates the migration of immune cells, such as T cells, monocytes, and macrophages, to sites of infection or injury by binding to its receptor, CCR5. 

Pro-Inflammatory Actions

CCL4 has important pro-inflammaotry actions that are involved in infections, autoimmune responses, and inflammatory conditions.

It contributes to the progression of autoimmune diseases, atherosclerosis, asthma, and some cancers by promoting a pro-inflammatory microenvironment. Elevated CCL4 levels correlate with increased immune cell recruitment and inflammatory mediators, potentially serving as a biomarker for disease prognosis. 

Memory T Cell Development

CCL4 plays an important role in the development and function of memory T cells. It helps guide these cells to the right locations, such as inflamed tissues or lymph nodes, where they can respond quickly to infections. CCL4 also enhances the interactions between memory T cells and dendritic cells. 

This chemokine signaling helps memory T cells remember past infections and respond effectively when the body reencounters the same pathogen.

Immune Modulation

Beyond its inflammatory functions, CCL4 has protective roles in certain experimental models of type 1 diabetes and may regulate immune responses by influencing T cell balance. 

Its complex role in disease progression and immune modulation makes CCL4 and its receptor, CCR5, potential therapeutic targets for conditions like autoimmune diseases, HIV infection, and inflammatory disorders.

CCL4 in Cardiovascular Disease

CCL4 plays an important role in the pathogenesis of cardiovascular diseases, particularly in atherosclerosis. It contributes to vascular inflammation by recruiting immune cells, including macrophages, to endothelial cells, which accelerates plaque formation and progression. 

Elevated CCL4 levels are associated with increased plaque vulnerability and can predict a higher risk of cardiovascular events, such as heart attacks and strokes. In addition, CCL4 promotes the release of inflammatory cytokines and enhances immune cell migration to sites of injury, exacerbating vascular damage. 

CCL4 in Diabetes

In diabetes, CCL4 is involved in the inflammatory processes that contribute to the development and progression of both type 1 and type 2 diabetes. 

In type 1 diabetes, CCL4 recruits macrophages that may damage insulin-producing β-cells in the pancreas. Although its role remains complex, some experimental models suggest CCL4 could also have protective effects by modulating immune responses. 

Elevated CCL4 levels in type 2 diabetes are linked to β-cell dysfunction and insulin resistance, particularly in patients with vascular complications. Research suggests that insulin therapy may reduce CCL4 expression, potentially alleviating inflammation and improving glucose regulation.

CCL4 in Autoimmune Diseases

CCL4 is a key mediator in autoimmune diseases, where it promotes inflammation by recruiting immune cells to affected tissues. It is implicated in conditions like rheumatoid arthritis, multiple sclerosis, and some inflammatory bowel diseases like Crohn’s disease, where it drives the chronic inflammation that characterizes these diseases. 

By attracting macrophages and other proinflammatory cells to sites of autoimmune activity, CCL4 contributes to tissue damage and disease progression. Additionally, CCL4's interaction with its receptor CCR5 has been linked to disease exacerbation, making it a potential target for therapeutic intervention aimed at reducing inflammation and modulating immune responses in autoimmune conditions.

CCL4 in Cancers

CCL4 affects the tumor microenvironment, at least in colorectal cancer, where resarch demonstrates that it contributes to tumor progression by promoting the recruitment of macrophages with a pro-tumor phenotype. 

Elevated CCL4 levels in tumors correlate with poor prognosis, as it supports a pro-inflammatory environment that aids tumor growth, angiogenesis, and metastasis. In CRC, CCL4's role in macrophage infiltration and its positive correlation with inflammatory mediators like TNF-α and VEGF make it a promising biomarker for assessing disease progression. 

CCL4 in HIV

CCL4 plays a key role in HIV-1 prevention by binding to the CCR5 co-receptor, blocking the virus from entering host cells. 

In HIV pre-exposure prophylaxis (PrEP), CCL4 production increases in response to antiretroviral drugs like FTC-TDF and FTC-TAF. This upregulation of CCL4 correlates with drug levels in plasma, suggesting that higher CCL4 levels help prevent HIV-1 infection by enhancing the immune response and blocking viral entry. 

CCL4 as a Biomarker

Given its central role in inflammation and immune responses, CCL4 levels are increasingly being measured in both research and clinical settings. While it is not a routine test in general health screenings, changes in CCL4 levels can serve as a biomarker for a range of conditions. 

When to Assess CCL4 Levels

CCL4 measurement is mostly used in research settings, particularly in infectious diseases, autoimmune disorders, and cancer studies. It can be valuable in understanding the role of CCL4 in disease processes, such as its potential to suppress or promote disease progression. 

However, in clinical practice, it may be used in the following situations:

• Clinical Research Studies: for understanding disease mechanisms, testing new therapies, or examining immune responses in conditions like infections, autoimmune conditions, or cancer.
• Monitoring Disease Activity: in some chronic inflammatory diseases, such as rheumatoid arthritis or multiple sclerosis, measuring CCL4 may provide insight into disease activity. However, other markers are more commonly used for this purpose.

CCL4 is not a routine test: it’s important to know that CCL4 is not typically included in general health screenings or used as a first-line test for common conditions.

Test Procedure and Interpretation

Measuring CCL4 levels is typically done through blood, serum, or, less commonly, cerebrospinal fluid (CSF) tests. In research, CCL4 is often used to study immune responses in these diseases, but its clinical utility remains focused on specific contexts.

While specific patient preparation isn't always required, acute infection or inflammation may affect the results. If the patient is experiencing an active infection, it might be beneficial to delay testing until the inflammation subsides or consider the test results in the context of the patient's current clinical presentation.

Normal Reference Ranges

Reference ranges for CCL4 can vary depending on the laboratory and the measurement method used. Clinicians should reference the lab's specific ranges for accurate interpretation.

Clinical Implications of Elevated Levels

High CCL4 levels often indicate active inflammation or immune activation. Elevated CCL4 levels are associated with various diseases, including:

• Infectious diseases like HIV, tuberculosis, and other viral infections.
• Inflammatory diseases such as rheumatoid arthritis, multiple sclerosis, and Crohn's disease.
• Cancer: CCL4 may play a role in tumor growth and metastasis in certain cancers, though its role in cancer is complex and varies by type. In some cancers, such as colorectal cancer, it may be used as a biomarker to inform prognosis.

Clinical Implications of Decreased Levels

While low CCL4 levels generally do not carry significant clinical implications, they may be observed. It's important to correlate these findings with the overall clinical picture, as the significance of decreased levels remains unclear in most cases.

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