1. Publication Information
- Link: https://www.science.org/doi/10.1126/sciimmunol.adu4944
- Journal: Science Immunology
- Impact Factor: Approx. 28 (Estimate)
- Journal Description: Science Immunology is a prestigious academic journal publishing cutting-edge research in the field of immunology. It covers a wide range of topics, from basic research on the immune system to the role of immunity in disease and the development of immunotherapies.
2. Summary
This study revealed that DNA-damaging anticancer drugs drastically alter the composition and function of cardiac resident macrophages. Experiments using mouse models showed that anticancer drugs such as doxorubicin activate p53 signaling, inducing necroptosis and apoptosis, thereby selectively depleting cardiac resident macrophages. Interestingly, monocytes subsequently reconstitute the cardiac macrophage compartment; however, these monocyte-derived macrophages differ from the original embryonic-derived macrophages and were found to possess protective effects against hypertension and ischemic heart disease. Furthermore, these monocyte-derived macrophages were revealed to suppress inflammation and attenuate myocardial remodeling via a type I interferon-dependent mechanism. This study highlights the previously unrecognized impact of anticancer drugs on the cardiac immune environment and deepens our understanding of monocyte plasticity and resident macrophage dynamics.
3. Background
With advances in cancer treatment, survival rates are improving, but cardiotoxicity caused by anticancer drugs has become a major issue. In particular, DNA-damaging anticancer drugs like doxorubicin are known to increase the risk of heart failure and ischemic heart disease. However, the detailed mechanisms regarding how these drugs affect the cardiac immune environment had not been fully elucidated. The heart contains immune cells called resident macrophages, which play important roles in maintaining cardiac homeostasis and tissue repair. In recent years, it has been suggested that these macrophages are also involved in the onset and progression of heart diseases. Therefore, understanding the impact of anticancer drugs on cardiac resident macrophages is crucial for developing strategies to mitigate chemotherapy-induced cardiotoxicity.
4. Key Findings (Molecular, Cellular, and Tissue Levels)
In this study, mouse models were used to analyze in detail the effects of DNA-damaging anticancer drugs, such as doxorubicin, on cardiac resident macrophages.
- Selective depletion of cardiac resident macrophages by anticancer drugs: It was confirmed that doxorubicin administration causes a marked decrease in cardiac resident macrophages. Investigation of molecular mechanisms revealed that doxorubicin activates p53 signaling, inducing necroptosis (programmed cell necrosis) and apoptosis (programmed cell death), leading to the selective removal of macrophages. To use an analogy, it is like flowers (macrophages) blooming in a garden (the heart) withering due to a herbicide (anticancer drug).
- Reconstitution of the cardiac macrophage compartment by monocyte-derived macrophages: It was found that over time after anticancer drug administration, bone marrow-derived monocytes infiltrate the heart and differentiate into macrophages, thereby reconstituting the cardiac macrophage compartment. However, these monocyte-derived macrophages differ in gene expression patterns from the original embryonic-derived macrophages and are suggested to have functional differences. This is analogous to planting a new type of flower (monocyte-derived macrophages) in the garden, resulting in a landscape different from before.
- Cardioprotective effects of monocyte-derived macrophages: Interestingly, monocyte-derived macrophages were found to have protective effects against hypertension and ischemic heart disease. These macrophages promote the production of type I interferons (IFN-I) and suppress inflammation, thereby attenuating myocardial remodeling. It is like the newly planted flowers (monocyte-derived macrophages) improving the garden soil and protecting it from pests.
5. Discussion / Implications
Anti-aging This study also offers interesting implications from an anti-aging perspective. It is known that with aging, the function of tissue-resident macrophages declines, causing chronic inflammation. The removal of macrophages by anticancer drugs and their subsequent reconstitution by monocyte-derived macrophages can be viewed as a form of “macrophage refresh.” However, whether monocyte-derived macrophages can maintain heart health in the long term needs to be clarified in future research.
Regenerative Medicine (MSC / EV) Regenerative medicine using mesenchymal stem cells (MSCs) or exosomes (EVs) is viewed as promising for treating heart diseases. MSCs/EVs are known to promote tissue repair via immunomodulatory effects, and macrophage functional regulation may be involved as one of the mechanisms. The results of this study may provide important information for developing new strategies to enhance the efficacy of cardiac regenerative therapies using MSCs/EVs.
Neuro-Organ Axis In recent years, interactions between the nervous system and organs have attracted attention. Nerve fibers are distributed in the heart and are involved in regulating cardiac function. Changes in cardiac resident macrophages caused by anticancer drugs may conceivably affect the function of the cardiac nervous system. For example, cytokines produced by macrophages might alter neurotransmission or influence neuronal survival. This point requires further detailed investigation in future studies.
7. Future Prospects
This study sheds new light on the mechanisms of chemotherapy-induced cardiotoxicity and may lead to the development of new therapeutic strategies to reduce the risk of cardiovascular disease in cancer survivors.
- Selective Macrophage Control: If we can control the differentiation of monocytes infiltrating the heart and increase the proportion of macrophages with cardioprotective effects, it may be possible to mitigate cardiotoxicity caused by anticancer drugs.
- Type I Interferon Therapy: Developing drugs that promote the production of type I interferons by monocyte-derived macrophages might suppress myocardial remodeling and improve cardiac function.
- Personalized Medicine: Personalized medicine, which selects the optimal anticancer drugs or combines cardioprotective therapies according to the patient’s genetic background and immune status, may become important.
8. Conclusion
This study demonstrated that DNA-damaging anticancer drugs drastically alter the composition and function of cardiac resident macrophages. The macrophage compartment depleted by these agents is subsequently repopulated by monocyte-derived macrophages. Notably, these recruited macrophages are distinct from the original resident population and have been shown to possess cardioprotective properties. This study sheds new light on the mechanisms underlying chemotherapy-induced cardiotoxicity and highlights potential avenues for developing new therapeutic strategies to mitigate the risk of cardiovascular disease in cancer survivors. Future research is warranted to investigate the long-term impact of these monocyte-derived macrophages and their interactions with the nervous system.
