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Immunometabolism. 2020;2(1):e200006. https://doi.org/10.20900/immunometab20200006
Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Molecular Cell Biology and Immunology, Amsterdam Cardiovascular Sciences, Cancer Center Amsterdam, De Boelelaan 1117, Amsterdam 1081 HZ, the Netherlands
Within atherosclerotic plaques, macrophages can take up cholesterol and thereby become lipid-laden cells. For long it has been thought that these foamy macrophages are the main contributors to chronic inflammatory responses in plaques. However, several publications lately highlighted that foamy plaque macrophages are less inflammatory than their non-foamy counterparts. Interestingly, a very recent EMBO Molecular Medicine paper by Wu et al. demonstrate that accumulation of lipids in tumor-associated macrophages (TAMs) elicits an immunosuppressive phenotype.
Macrophage translates as “big eater”, from Greek (macros = big and phagein = eat) and these innate immune cells engulf and kill microbes to protect us against infections. As proficient phagocytes macrophages also readily ingest lipids to acquire a foamy appearance. Foam cells are prevalent in all stages of atherosclerosis, leading to the common belief that they are the crucial drivers of chronic inflammation during this cholesterol-driven inflammatory disease. Yet, recent findings in cardiovascular research elicited a paradigm shift and highlight that “normal” macrophages, as opposed to lipid-laden foamy macrophages, are the main producers of inflammatory factors [1–3] (Figure 1).
Lipid-laden macrophages now also gained attention outside the atherosclerosis field and crossed borders to cancer research. Tumor-associated macrophages (TAMs) support tumor growth and metastasis by hampering anti-tumor immune responses and by facilitating angiogenesis.
Wu and colleagues recently reported in EMBO Molecular Medicine that this immunosuppressive phenotype of TAMs results from the accumulation of lipid droplets and associated metabolic rewiring . They found lipid droplets to accumulate in TAMs from colorectal cancer patients. While numbers of macrophages did not differ between benign and tumor tissue in these patients, lipid droplet accumulation was specifically detected in TAMs. Hence, the quality but not necessarily the quantity of TAMs could serve as a prognostic prediction of cancer.
Lipid droplet-derived fatty acids increased mitochondrial respiration and this metabolic shift towards increased fatty acid oxidation directly regulated the immunosuppressive function of macrophages. Consequently, disrupting lipid droplet formation in TAMs in vivo prevented the formation of a pro-tumor macrophage phenotype and impeded tumor growth. As such, the authors propose a potential therapeutic strategy that targets pro-tumor macrophages at an immunometabolic level.
Altogether, these discoveries in cardiovascular and cancer research indicate that lipid accumulation does not directly drive inflammation and rather elicits a suppressive macrophage phenotype. As such, we could consider lipid-laden macrophages as laidback couch potatoes that hang out without stoking inflammation and immunity? Maybe this is not the best description since they are not just passive and can actively suppress inflammation and anti-tumor immunity. Undoubtedly, recent literature demonstrates that lipid-laden macrophage are clearly less inflammatory than the current dogma states. This challenges the research community to have a more open vision on macrophage subtypes and their roles in disease progression.
The author declares that he has no conflicts of interest.
JVdB received a VENI grant from ZonMW (91615052), a Netherlands Heart Foundation Junior Postdoctoral grant (2013T003), and Senior Fellowship (2017T048), a proof-of-concept grant from Cancer Center Amsterdam (CCA), a PhD grant from Amsterdam Cardiovascular Sciences (ACS) and a transnational European Research Area Network on Cardiovascular Diseases (ERA-CDV) grant.
The author thanks Shuqi Yang and Theresa Ramalho for their discussions and input when writing this commentary.
Van den Bossche J. Lipid-Laden Macrophages cross the Border to Cancer. Immunometabolism. 2020;2(1):e200006. https://doi.org/10.20900/immunometab20200006