CCR4 Deficiency in a Mouse Model Leads to Increased Early Atherosclerosis Development

Główne pojęcia

CCR4 expression on Tregs plays a critical role in regulating early atherosclerosis development by suppressing proinflammatory Th1 cell responses and mediating Treg migration to the aorta.

Streszczenie

• Bibliographic Information: While the provided text resembles a research paper, it lacks complete bibliographic information.
• Research Objective: This study investigates the role of C-C chemokine receptor 4 (CCR4) in the development of early atherosclerotic lesions, focusing on its impact on CD4+ T cell immune responses in a mouse model.
• Methodology: The researchers used a mouse model with CCR4 deficiency on an Apoe−/− background. They analyzed atherosclerotic lesions, immune cell populations, and gene expression in various tissues. In vitro experiments, including T cell suppression assays and co-culture systems, were employed to investigate the mechanisms of CCR4 action.
• Key Findings:
  • CCR4 deficiency led to accelerated early atherosclerotic lesion development in the aortic root, characterized by increased macrophage and CD4+ T cell infiltration.
  • CCR4 deficiency augmented Th1 cell responses in peripheral lymphoid tissues, para-aortic lymph nodes, and the atherosclerotic aorta.
  • CCR4 expression on Tregs was found to be crucial for their suppressive function and migration to the atherosclerotic aorta.
  • CCR4-deficient Tregs exhibited impaired suppression of Th1 cell responses, likely due to disrupted interactions with dendritic cells.
  • Treg transfer experiments confirmed the protective role of CCR4 in early atherosclerosis development.
• Main Conclusions: CCR4 expression, particularly on Tregs, plays a protective role against early atherosclerosis development. This protection is mediated by suppressing proinflammatory Th1 cell responses and facilitating Treg migration to the aorta.
• Significance: This study identifies CCR4 as a potential therapeutic target for atherosclerosis. Targeting CCR4 or its related signaling pathways could help modulate the balance between pro-inflammatory and anti-inflammatory immune responses, potentially limiting atherosclerosis progression.
• Limitations and Future Research: The study primarily focuses on early atherosclerosis development in a mouse model. Further research is needed to determine the role of CCR4 in later stages of atherosclerosis and its relevance to human disease. Investigating the translational potential of targeting CCR4 for atherosclerosis treatment in humans is also warranted.

Statystyki

Ccr4−/−Apoe−/− mice exhibited a significant increase in atherosclerotic lesion size in the aortic sinus compared to Apoe−/− mice (aortic sinus mean plaque area: control Apoe−/− mice: 1.46 ± 0.50 ×105 μm2 versus Ccr4−/−Apoe−/−: 2.04 ± 0.82 ×105 μm2, P<0.05).
The atherosclerotic lesions of Ccr4−/−Apoe−/− mice showed a 20% increase in macrophage accumulation and a marked 42% increase in CD4+ T cell infiltration compared to Apoe−/− mice.
CCR4 deficiency significantly impaired the suppressive function of Tregs isolated from hypercholesterolemic mice.
There was a significant reduction in the proportion of CCR4-deficient Kaede-expressing Tregs in the aorta of recipient Apoe−/− mice.

Cytaty

"Thus, we revealed a previously unrecognized role for CCR4 in controlling the early stage of atherosclerosis via Treg-dependent regulation of proinflammatory T cell responses."
"Our data suggest that CCR4 is an important negative regulator of atherosclerosis."

Kluczowe wnioski z

C-C chemokine receptor 4 deficiency exacerbates early atherosclerosis in mice

by Tanaka,T., S... o www.biorxiv.org 08-19-2024

https://www.biorxiv.org/content/10.1101/2024.08.16.608245v1

Głębsze pytania

How might the findings of this study influence the development of novel therapeutics for atherosclerosis, particularly those targeting the immune system?

This study highlights the potential of targeting the CCL17/CCL22-CCR4 axis, particularly CCR4 expressed on Tregs, as a novel therapeutic strategy for atherosclerosis. Here's how:

Boosting Treg migration to atherosclerotic plaques: The study demonstrates that CCR4 is essential for Treg migration to the aorta. Therapeutics that enhance CCR4 expression on Tregs or increase the availability of its ligands, CCL17 and CCL22, specifically within atherosclerotic lesions, could promote Treg accumulation at the site of inflammation. This targeted approach could help dampen the inflammatory response within the plaque and potentially stabilize it.
Enhancing Treg suppressive function: The research shows that CCR4 deficiency impairs the ability of Tregs to suppress pro-inflammatory Th1 cell responses. Developing therapies that enhance CCR4 signaling in Tregs could restore their suppressive function. This could involve directly activating CCR4 or targeting downstream signaling pathways that are crucial for Treg-mediated suppression of Th1 cells.
Combination therapies: Targeting CCR4 could be particularly effective in combination with existing or emerging therapies for atherosclerosis. For example, combining CCR4 agonists with lipid-lowering drugs could provide a multifaceted approach to managing atherosclerosis by addressing both lipid levels and the inflammatory component of the disease.
Challenges and Considerations:

Specificity and off-target effects: Developing therapies that specifically target CCR4 on Tregs while minimizing effects on other CCR4-expressing cells, such as Th2 and Th17 cells, will be crucial to avoid unwanted immune reactions.
Translatability to humans: While the study was conducted in mice, further research is needed to confirm the relevance of these findings to human atherosclerosis and to assess the safety and efficacy of CCR4-targeted therapies in humans.

Could other factors besides CCR4 deficiency contribute to the observed increase in Th1 cell responses and accelerated atherosclerosis in the mouse model?

While the study strongly implicates CCR4 deficiency in the observed effects, other factors could contribute to the increased Th1 cell responses and accelerated atherosclerosis in the mouse model:

Microbiome dysbiosis: The gut microbiome plays a role in shaping immune responses, and alterations in its composition (dysbiosis) have been linked to atherosclerosis. It's possible that CCR4 deficiency indirectly influences the gut microbiome, leading to changes that promote Th1 cell differentiation and inflammation.
Off-target effects of CCR4 deletion: While the study focuses on T cells, CCR4 is expressed on other immune cells. Its deletion could have unforeseen consequences on these cells, indirectly influencing the immune balance and atherosclerosis progression.
Influence on other chemokine receptors: CCR4 deficiency might lead to compensatory changes in the expression or function of other chemokine receptors on T cells, potentially contributing to the observed Th1 skewing.
Environmental factors: Factors like diet, stress, and infections can influence both the immune system and atherosclerosis development. These factors were not explicitly investigated in the study and could contribute to the observed phenotype.

What are the broader implications of understanding the intricate balance between pro-inflammatory and anti-inflammatory immune responses in the context of chronic diseases beyond atherosclerosis?

The study's findings underscore the critical importance of a balanced immune response in maintaining health and preventing chronic diseases. Here are broader implications beyond atherosclerosis:

Autoimmune diseases: In conditions like rheumatoid arthritis, type 1 diabetes, and multiple sclerosis, the immune system mistakenly attacks the body's own tissues. Understanding how to dampen pro-inflammatory responses and promote anti-inflammatory mechanisms, similar to the role of Tregs in atherosclerosis, is crucial for developing effective treatments for these diseases.
Cancer: While an effective immune response is essential for fighting cancer, chronic inflammation can contribute to tumor development and progression. Strategies that re-establish immune balance by boosting anti-tumor immunity while controlling excessive inflammation are being explored as potential cancer therapies.
Neurodegenerative diseases: Chronic inflammation in the brain is increasingly recognized as a contributing factor to neurodegenerative diseases like Alzheimer's and Parkinson's. Modulating the immune response to reduce neuroinflammation holds promise for slowing or preventing the progression of these debilitating conditions.
Metabolic disorders: Chronic low-grade inflammation is a hallmark of metabolic disorders like obesity and type 2 diabetes. Understanding the interplay between immune cells, metabolism, and inflammation is crucial for developing interventions that target the root causes of these diseases.
Overall, this study highlights the importance of a balanced immune response in maintaining health and preventing chronic diseases. By unraveling the complex interactions between pro- and anti-inflammatory mechanisms, researchers can develop targeted therapies that restore immune balance and improve outcomes for a wide range of conditions.