Atherosclerotic cardiovascular disease is a progressive pathological process initiated by the accumulation of cholesterol-rich lipoproteins within the intima layer of the arterial wall. These particles ultimately lead to the production of chemoattractant cues for circulating monocytes that transmigrate across the endothelial layer to reach the intima and then differentiate to macrophages to become cholesterol-laden foam cells. During lesion development, macrophages promote local inflammation and plaque weakening by degrading extracellular matrix components such as collagen fibers, which can evolve in the rupture of the lesion and thrombus formation (Newby et al., 2009).

Conventional therapies aim to lower plasma cholesterol to mitigate the progression of atherosclerosis. Novel strategies are currently under development to stimulate the resolution of plaque inflammation more directly, and eventually a reduction in lesion size, in a process named atherosclerosis regression (Goldberg et al., 2020). Among these strategies, the modulation of CD4⁺ regulatory T cells (Tregs) number is gaining interest over the past years since the discovery that regressing lesions are enriched in Tregs, where they promote plaque stabilization and repair (Andersson et al., 2010; Witztum and Lichtman, 2014). Tregs typically express the surface marker CD25, which has been utilized to target and eliminate Tregs (Onda et al., 2019; Sharma et al., 2020). However, strategies to deplete CD25⁺ Tregs do not affect CD25^- Tregs, which possess similar immunomodulatory properties as CD25⁺ Tregs (Couper et al., 2007). Among the different Tregs markers, the forkhead box P3 (FoxP3) acts as lineage specification factor regulating gene expression of proteins implicated in the immunosuppressive activity of these cells (Fontenot et al., 2005). Cell culture studies show that retinoic acid, the transcriptionally active form of vitamin A, promotes Treg differentiation by upregulating FoxP3 expression (Elias et al., 2008); however, whether dietary vitamin A affects Tregs during atherosclerosis development and resolution remains unanswered.

Humans obtain vitamin A primarily from β-carotene and other provitamin A carotenoids present in most fruits and vegetables. Upon absorption, provitamin A carotenoids are cleaved by the action of β-carotene oxygenase 1 (BCO1), the limiting enzyme in vitamin A formation (von Lintig and Vogt, 2000). Our data show that the enzymatic activity of BCO1 mediates the bioactive actions of β-carotene in various preclinical models of obesity and atherosclerosis (Hessel et al., 2007; Amengual et al., 2013; Amengual et al., 2011; Lobo et al., 2010; Zhou et al., 2020; Coronel et al., 2022). We showed that the dietary supplementation with β-carotene delays atherosclerosis progression by reducing cholesterol hepatic secretion in low-density lipoprotein receptor (LDLR)-deficient (Ldlr^-/-) mice (Zhou et al., 2020). We also reported that subjects harboring a genetic variant linked to greater BCO1 activity were associated with a reduction in plasma cholesterol (Amengual et al., 2020).

In this study, we tested the effect of dietary β-carotene on atherosclerosis resolution in two independent experimental models. We characterized plaque composition by probing for macrophage and collagen contents, two parameters utilized to characterize atherosclerotic lesions undergoing resolution (Amengual et al., 2021; Josefs et al., 2021; Josefs et al., 2020; Barrett et al., 2019). Lastly, we utilized Bco1^-/- mice and CD25⁺ Treg depletion experiments in Foxp3^EGFP mice to tease out the direct implications of vitamin A formation and Tregs on atherosclerosis resolution.

Seminal studies showed that β-carotene delays atherosclerosis progression in various experimental models by reducing plasma cholesterol levels (Relevy et al., 2015; Harari et al., 2008; Shaish et al., 1995), while greater levels of circulating β-carotene and retinoic acid are associated with lower risk of cardiovascular disease in people (Wang et al., 2014; Huang et al., 2018). In 2020, we demonstrated that these effects depend on BCO1 activity in mice, and that a genetic variant in the BCO1 gene is associated with a reduction in plasma cholesterol levels in people (Zhou et al., 2020; Amengual et al., 2020). Our study shows that β-carotene promotes atherosclerosis resolution in two independent experimental models in a BCO1-dependent manner. Treg depletion studies revealed that dietary β-carotene favors Treg expansion in resolving lesions. Together, these findings identify dietary β-carotene and its conversion to vitamin A as a promising strategy to ameliorate plaque burden not only by delaying atherosclerosis progression, but also by reversing atherosclerosis inflammation.

Carotenoids are the main source of vitamin A in human diet, and the only source of this vitamin in strict vegetarians (Grune et al., 2010). Among those carotenoids with provitamin A activity, β-carotene is the most abundant in our diet and the only compound capable of producing two vitamin A molecules. Vitamin A is required for vision, embryo development, and immune cell maturation, making β-carotene a crucial nutrient for human health (Coronel et al., 2019). Unlike preformed vitamin A, the intestinal uptake of carotenoids is a protein-mediated process that depends on vitamin A status. This regulatory mechanism prevents the excessive uptake of provitamin A carotenoids to avoid vitamin A toxicity (Lobo et al., 2013; Seino et al., 2008).

BCO1 is the only enzyme in mammals capable of synthesizing vitamin A from carotenoids (von Lintig and Vogt, 2000; Amengual et al., 2013). Therefore, it is not surprising that SNPs in the BCO1 gene are associated to alterations in circulating carotenoids including β-carotene (Clifford et al., 2013; Yabuta et al., 2016; Moran et al., 2019). We recently described that subjects harboring at least a copy of rs6564851-T allele, which increases BCO1 activity (Lietz et al., 2012), show a reduction in total cholesterol and non-HDL-C in comparison to those with two copies of the rs6564851-G variant (Amengual et al., 2020). A recent study revealed that this variant is also associated with triglyceride levels in middle-aged individuals (León-Reyes et al., 2022), implicating BCO1 activity as a novel regulator of plasma lipid profile. These studies provide a clinical relevance to studies performed in rodents and rabbits in which β-carotene-rich diets reduce plasma cholesterol and mitigate the development of atherosclerosis (Zhou et al., 2020; Relevy et al., 2015; Harari et al., 2008; Shaish et al., 1995).

Carotenoids, including β-carotene, possess antioxidant properties in lipid-rich environments (Rodriguez-Concepcion et al., 2018). The development of Bco1^-/- mice of contributed to solving a long-lasting controversy in the carotenoid field by dissecting the biological effects of intact β-carotene and its role in vitamin A formation. When Bco1^-/- mice are fed β-carotene, these mice accumulate large amounts of this compound in tissues and plasma (Hessel et al., 2007). In 2011, we reported that wild-type mice fed β-carotene exhibited a reduction in adipose tissue size. Bco1^-/- mice subjected to the same experimental conditions did not show differences in adipose tissue size in comparison to control-fed mice despite accumulating large amounts of β-carotene in this tissue (Coronel et al., 2022). We recently overexpressed BCO1 in the adipose tissue of Bco1^-/- mice fed β-carotene. Under these conditions, we observed an increase in vitamin A levels including retinoic acid and a reduction in adipose tissue size (Coronel et al., 2022). These effects are in line with those reported by Palou’s group utilizing both dietary vitamin A and retinoic acid supplementation, which promotes fatty acid oxidation and thermogenesis in various experimental models (Bonet et al., 2020; Amengual et al., 2018; Granados et al., 2013; Amengual et al., 2012; Amengual et al., 2010; Amengual et al., 2008; Mercader et al., 2006; Felipe et al., 2005; Felipe et al., 2004; Puigserver et al., 1996; Berry and Noy, 2009).

In 2020, we confirmed the implication of BCO1 activity and vitamin A in the development of atherosclerosis. We compared the effect of β-carotene on Ldlr^-/- and Ldlr^-/-Bco1^-/- mice using the same experimental diets utilized in this study (Supplementary file 1). In alignment with our clinical data, β-carotene reduced total cholesterol and non-HDL-C in Ldlr^-/- mice, but not in Ldlr^-/-Bco1^-/- mice (Zhou et al., 2020; Amengual et al., 2020). β-Carotene supplementation during atherosclerosis resolution, either in Western or standard diets, failed to improve plasma lipids in comparison to resolution–control groups (Figures 1B and 2A). This discrepancy could be attributed to the duration of the β-carotene feedings: 12 wk in our progression study vs. 3–4 wk in our resolution studies (Zhou et al., 2020). Another possibility is that the effect of β-carotene is only evident in mice displaying elevated plasma lipid levels such as reported in studies using Ldlr^-/- and apolipoprotein E-deficient mice fed atherogenic diets (Zhou et al., 2020; Relevy et al., 2015; Harari et al., 2008).

In our atherosclerosis progression study, we attributed the effects of dietary β-carotene on plasma lipids to the formation of retinoic acid in the liver. We showed that retinoic acid treatment decreased cholesterol and triglyceride hepatic secretion rates in cultured hepatocytes and wild-type mice, suggesting that the effects of β-carotene on plasma lipid profile depend on the lipidation of hepatic lipoprotein particles (Zhou et al., 2020). Whether BCO1 activity is associated with the development of atherosclerotic cardiovascular disease in humans, however, remains unexplored.

Besides its effects on lipid metabolism, retinoic acid modulates immune cell function (Miller et al., 2020). Exogenous retinoic acid promotes alternative macrophage activation in various cell culture models, and skews naïve T cells to anti-inflammatory Tregs by directly upregulating the transcription factor FoxP3 (He et al., 2021; Mucida et al., 2007). The expression of FoxP3 is necessary and sufficient for the anti-inflammatory phenotype of Tregs (Fontenot et al., 2005; Hori et al., 2003). Studies carried out by Loke’s group highlighted the interplay between alternative macrophage activation and Treg differentiation, a process that was proposed to be mediated by the production and release of retinoic acid by the macrophage (Gundra et al., 2014; Broadhurst et al., 2012). This hypothesis has not been demonstrated to date, partially due to the technical difficulty to quantify retinoic acid production in biological samples (Kane et al., 2008). We recently overcame this limitation and demonstrated for the first time that alternatively activated macrophages produce and release retinoic acid in a STAT6-dependent manner (Pinos et al., 2023). We also demonstrated that exogenous retinoic synergizes with interleukin 4 (IL4) to stimulate the expression of arginase 1, which is considered an anti-inflammatory marker in murine macrophages (Pinos et al., 2023; Murray et al., 2014). Arginase 1 catalyzes the production of ornithine, which is a precursor of proline (Szondi et al., 2021). Together with its derivative hydroxyproline, proline is a key limiting amino acid in the synthesis of collagen. These results indicate that the combination of retinoic acid with anti-inflammatory signals typically present during regressing lesions could favor atherosclerosis resolution by stimulating collagen deposition by the macrophage.

Our PCR data in liver homogenates show β-carotene supplementation upregulates Cyp26a1 expression in the liver, which, together with Cyp26b1 and Cyp26c1, are widely considered as surrogate markers for retinoic signaling in tissues (Figure 1—figure supplement 1B, Abu-Abed et al., 2002; Ross and Zolfaghari, 2011). Cyp26 family members are responsible for the degradation of intracellular retinoic acid, and their expression is regulated by retinoic acid response elements in their promoter (Abu-Abed et al., 2002; Ross and Zolfaghari, 2011). To examine whether β-carotene also stimulates retinoic acid signaling in the atherosclerotic lesion, we stained the lesions of Foxp3^EGFP mice with Cyp26b1 (Figure 5H and I). Among the three Cyp26s, we selected Cyp26b1 based on our recent RNAseq data in murine bone marrow-derived macrophages exposed to retinoic acid (Pinos et al., 2023). We observed that Cyp26b1 was the only Cyp26 family member responsive to retinoic acid in macrophages. Our immunostaining showed that Cyp26b1 co-localizes with the macrophage marker CD68, in agreement with results obtained in human lesions showing that CYP26B1 are present in macrophage-rich areas (Krivospitskaya et al., 2012). This study also reported an association between aggravated atherosclerosis with an SNP in the CYP26B1 gene with a greater retinoic acid catabolic activity (Krivospitskaya et al., 2012). These data suggest that greater retinoic acid levels in the lesion could decrease atherogenesis in humans, in agreement with our preclinical findings.

Despite the upregulation of Cyp26b1 expression, Treg expansion in regressing lesions in response to β-carotene was partially suppressed in mice injected with anti-CD25 (Figure 4H). To rule out intact β-carotene as the driving factor responsible for these effects, we quantified the number of Tregs in our experiment using Bco1^-/- mice. As expected, both resolution groups displayed a greater number of Tregs in comparison to baseline mice, although we did not observe any effect in response to β-carotene (Figure 3—figure supplement 1D and E). These data suggest that vitamin A formation is required for Treg expansion in the atherosclerotic lesion of mice. To our knowledge, this is the first report showing that a dietary intervention with a nutrient administered at physiological concentrations can modulate Treg levels in the atherosclerotic lesion. As a reference, our diets were supplemented with 50 mg of β-carotene/kg in comparison to 80 mg of β-carotene/kg in carrots (USDA Database).

Our HPLC analyses in liver and plasma revealed that our experimental approach did not result in vitamin A deficiency despite feeding our mice vitamin A-deficient diets for several weeks to develop atherosclerosis. This was not surprising since mice are notably resistant to vitamin A deficiency. Protocols to develop vitamin A deficiency in wild-type mice require feeding the dams a vitamin A-deficient diet during pregnancy through weaning (Gundra et al., 2017), although the use of genetic models lacking key proteins in vitamin A transport, uptake, or storage are more adequate and time-efficient (Quadro et al., 1999; O’Byrne et al., 2005; Amengual et al., 2014). Future experiments utilizing these genetic models could shed light on the role of vitamin A deficiency on Treg expansion and its consequence on atherosclerosis resolution.

To establish a direct link between the effect of β-carotene supplementation and Tregs in our experimental model, we decided to deplete Tregs in Foxp3^EGFP mice by infusing them with anti-CD25, following Sharma and colleagues’ approach (Sharma et al., 2020). However, our data show that this strategy failed to completely deplete Tregs as previously reported by other investigators (Couper et al., 2007; Hayes et al., 2020). CD25^- Tregs remained in circulation and tissues including aortic lesions (Figure 4E–H, Figure 4—figure supplement 1). It is possible that the conversion of β-carotene to retinoic acid favored Treg expansion by specifically favoring CD25^- Treg proliferation, which are insensitive to anti-CD25.

CD25 is a crucial component of the IL2 receptor and it is expressed in CD4⁺ T cell subsets other than Tregs (CD4⁺CD25⁺FoxP3^-) (Wing et al., 2002). Therefore, strategies targeting FoxP3⁺ cells directly are an attractive approach to specifically dissect the role of Tregs in our experimental model. For example, the use of Foxp3^DTR mice (#016958, Jackson Labs), which express the diphtheria toxin receptor, would allow us to specifically deplete FoxP3⁺ cells independently of the expression of CD25 (Kim et al., 2007). This approach would also eliminate CD8⁺CD25⁺FoxP3⁺ Tregs, a relatively new Treg subpopulation (Churlaud et al., 2015). However, Treg depletion in Foxp3^DTR mice requires injections with diphtheria toxin, which can result in potential adverse effects under certain experimental conditions (Christiaansen et al., 2014). Future studies dissecting the contribution of T cell subpopulations and the role vitamin A and other nutrients could play in their differentiation are needed to fully understand their role during atherosclerosis resolution.

Whether β-carotene supplementation during atherosclerosis resolution alters Treg content in other organs and disease models was outside the scope of this study. For example, an increase in Treg number in developing tumors could result in the reprogramming of pro-inflammatory macrophages toward resolving macrophages that could contribute to tumor expansion (Ohue and Nishikawa, 2019). In summary, partial Treg depletion was sufficient to mitigate the effects of β-carotene on plaque composition during the resolution of atherosclerosis, providing a direct link between β-carotene and Treg number (Figure 5A–I).

Another question remains unanswered: what is the source of vitamin A that favors Treg expansion in the lesion? Our HPLC analyses show that circulating β-carotene in wild-type mice is marginal, although hepatic vitamin A stores highlight an increase in vitamin A formation (Figures 1H and 3A and B). It is not clear whether naïve T cells express BCO1, which would enable them to locally produce vitamin A and its derivative retinoic acid. Previous work has related tissue macrophages as responsible for retinoic acid production and suggested that these cells would release it to signal nearby naïve T cells, which, in turn, could differentiate into Tregs. Retinoic acid could have originated from β-carotene or retinol/retinyl esters stored in the cell, although our RNA-sequencing analysis revealed that BCO1 expression in plaque macrophages is relatively limited (Zhou et al., 2020). Plaque macrophages, and T cells to a lesser extent, express various scavenger receptors that have been linked to the uptake of retinoids and carotenoids such as the scavenger receptor class BI, lipoprotein lipase, and the cluster of differentiation 36 (Reboul, 2019). Determining whether naïve T cells rely on plaque macrophages to obtain retinoids and activate FoxP3 to differentiate into Treg is not clear to this day.

In summary, we report for the first time that vitamin A production from β-carotene favors Treg expansion in the atherosclerotic lesion, a process that contributes to atherosclerosis resolution. Together with the cholesterol-lowering effects of β-carotene described in the past, it unveils a dual role of dietary β-carotene and the enzyme BCO1: (1) BCO1 delays atherosclerosis progression by reducing plasma cholesterol and (2) favors atherosclerosis resolution by modulating Treg levels and macrophage polarization status.

All data generated or analyzed during this study are included in the manuscript and supporting files.

1. 1. Abu-Abed S
   2. MacLean G
   3. Fraulob V
   4. Chambon P
   5. Petkovich M
   6. Dollé P

   (2002) Differential expression of the retinoic acid-metabolizing enzymes CYP26A1 and CYP26B1 during murine organogenesis

   Mechanisms of Development 110:173–177.

   https://doi.org/10.1016/s0925-4773(01)00572-x

   • PubMed
   • Google Scholar
2. 1. Ait-Oufella H
   2. Salomon BL
   3. Potteaux S
   4. Robertson A-KL
   5. Gourdy P
   6. Zoll J
   7. Merval R
   8. Esposito B
   9. Cohen JL
   10. Fisson S
   11. Flavell RA
   12. Hansson GK
   13. Klatzmann D
   14. Tedgui A
   15. Mallat Z

   (2006) Natural regulatory T cells control the development of atherosclerosis in mice

   Nature Medicine 12:178–180.

   https://doi.org/10.1038/nm1343

   • PubMed
   • Google Scholar
3. 1. Amengual J
   2. Ribot J
   3. Bonet ML
   4. Palou A

   (2008) Retinoic acid treatment increases lipid oxidation capacity in skeletal muscle of mice

   Obesity 16:585–591.

   https://doi.org/10.1038/oby.2007.104

   • PubMed
   • Google Scholar
4. 1. Amengual J
   2. Ribot J
   3. Bonet ML
   4. Palou A

   (2010) Retinoic acid treatment enhances lipid oxidation and inhibits lipid biosynthesis capacities in the liver of mice

   Cellular Physiology and Biochemistry 25:657–666.

   https://doi.org/10.1159/000315085

   • PubMed
   • Google Scholar
5. 1. Amengual J
   2. Gouranton E
   3. van Helden YGJ
   4. Hessel S
   5. Ribot J
   6. Kramer E
   7. Kiec-Wilk B
   8. Razny U
   9. Lietz G
   10. Wyss A
   11. Dembinska-Kiec A
   12. Palou A
   13. Keijer J
   14. Landrier JF
   15. Bonet ML
   16. von Lintig J

   (2011) Beta-carotene reduces body adiposity of mice via BCMO1

   PLOS ONE 6:e20644.

   https://doi.org/10.1371/journal.pone.0020644

   • PubMed
   • Google Scholar
6. 1. Amengual J
   2. Petrov P
   3. Bonet ML
   4. Ribot J
   5. Palou A

   (2012) Induction of carnitine palmitoyl transferase 1 and fatty acid oxidation by retinoic acid in HepG2 cells

   The International Journal of Biochemistry & Cell Biology 44:2019–2027.

   https://doi.org/10.1016/j.biocel.2012.07.026

   • PubMed
   • Google Scholar
7. 1. Amengual J
   2. Widjaja-Adhi MAK
   3. Rodriguez-Santiago S
   4. Hessel S
   5. Golczak M
   6. Palczewski K
   7. von Lintig J

   (2013) Two carotenoid oxygenases contribute to mammalian provitamin A metabolism

   The Journal of Biological Chemistry 288:34081–34096.

   https://doi.org/10.1074/jbc.M113.501049

   • PubMed
   • Google Scholar
8. 1. Amengual J
   2. Zhang N
   3. Kemerer M
   4. Maeda T
   5. Palczewski K
   6. Von Lintig J

   (2014) STRA6 is critical for cellular vitamin A uptake and homeostasis

   Human Molecular Genetics 23:5402–5417.

   https://doi.org/10.1093/hmg/ddu258

   • PubMed
   • Google Scholar
9. 1. Amengual J
   2. García-Carrizo FJ
   3. Arreguín A
   4. Mušinović H
   5. Granados N
   6. Palou A
   7. Bonet ML
   8. Ribot J

   (2018) Retinoic acid increases fatty acid oxidation and irisin expression in skeletal muscle cells and impacts irisin in vivo

   Cellular Physiology and Biochemistry 46:187–202.

   https://doi.org/10.1159/000488422

   • PubMed
   • Google Scholar
10. 1. Amengual J
    2. Coronel J
    3. Marques C
    4. Aradillas-García C
    5. Morales JMV
    6. Andrade FCD
    7. Erdman JW
    8. Teran-Garcia M

    (2020) β-carotene oxygenase 1 activity modulates circulating cholesterol concentrations in mice and humans

    The Journal of Nutrition 150:2023–2030.

    https://doi.org/10.1093/jn/nxaa143

    • PubMed
    • Google Scholar
11. 1. Amengual J
    2. Ogando Y
    3. Nikain C
    4. Quezada A
    5. Qian K
    6. Vaisar T
    7. Fisher EA

    (2021) Short-Term Acyl-CoA:Cholesterol acyltransferase inhibition, combined with apoprotein a1 overexpression, promotes atherosclerosis inflammation resolution in mice

    Molecular Pharmacology 99:175–183.

    https://doi.org/10.1124/molpharm.120.000108

    • PubMed
    • Google Scholar
12. 1. Andersson J
    2. Libby P
    3. Hansson GK

    (2010) Adaptive immunity and atherosclerosis

    Clinical Immunology 134:33–46.

    https://doi.org/10.1016/j.clim.2009.07.002

    • PubMed
    • Google Scholar
13. 1. Barrett TJ
    2. Distel E
    3. Murphy AJ
    4. Hu J
    5. Garshick MS
    6. Ogando Y
    7. Liu J
    8. Vaisar T
    9. Heinecke JW
    10. Berger JS
    11. Goldberg IJ
    12. Fisher EA

    (2019) Apolipoprotein AI) promotes atherosclerosis regression in diabetic mice by suppressing myelopoiesis and plaque inflammation

    Circulation 140:1170–1184.

    https://doi.org/10.1161/CIRCULATIONAHA.119.039476

    • PubMed
    • Google Scholar
14. 1. Basu D
    2. Hu Y
    3. Huggins L-A
    4. Mullick AE
    5. Graham MJ
    6. Wietecha T
    7. Barnhart S
    8. Mogul A
    9. Pfeiffer K
    10. Zirlik A
    11. Fisher EA
    12. Bornfeldt KE
    13. Willecke F
    14. Goldberg IJ

    (2018) Novel reversible model of atherosclerosis and regression using oligonucleotide regulation of the LDL receptor

    Circulation Research 122:560–567.

    https://doi.org/10.1161/CIRCRESAHA.117.311361

    • PubMed
    • Google Scholar
15. 1. Benjamini Y
    2. Drai D
    3. Elmer G
    4. Kafkafi N
    5. Golani I

    (2001) Controlling the false discovery rate in behavior genetics research

    Behavioural Brain Research 125:279–284.

    https://doi.org/10.1016/s0166-4328(01)00297-2

    • PubMed
    • Google Scholar
16. 1. Berry DC
    2. Noy N

    (2009) All-trans-retinoic acid represses obesity and insulin resistance by activating both PPAR{beta}/{delta} and RAR

    Molecular and Cellular Biology 29:3286–3296.

    https://doi.org/10.1128/MCB.01742-08

    • PubMed
    • Google Scholar
17. 1. Bonet ML
    2. Ribot J
    3. Galmés S
    4. Serra F
    5. Palou A

    (2020) Carotenoids and carotenoid conversion products in adipose tissue biology and obesity: Pre-clinical and human studies

    Biochimica et Biophysica Acta. Molecular and Cell Biology of Lipids 1865:158676.

    https://doi.org/10.1016/j.bbalip.2020.158676

    • PubMed
    • Google Scholar
18. 1. Broadhurst MJ
    2. Leung JM
    3. Lim KC
    4. Girgis NM
    5. Gundra UM
    6. Fallon PG
    7. Premenko-Lanier M
    8. McKerrow JH
    9. McCune JM
    10. Loke P

    (2012) Upregulation of retinal dehydrogenase 2 in alternatively activated macrophages during retinoid-dependent type-2 immunity to helminth infection in mice

    PLOS Pathogens 8:e1002883.

    https://doi.org/10.1371/journal.ppat.1002883

    • PubMed
    • Google Scholar
19. 1. Christiaansen AF
    2. Boggiatto PM
    3. Varga SM

    (2014) Limitations of Foxp3(+) Treg depletion following viral infection in DEREG mice

    Journal of Immunological Methods 406:58–65.

    https://doi.org/10.1016/j.jim.2014.03.005

    • PubMed
    • Google Scholar
20. 1. Churlaud G
    2. Pitoiset F
    3. Jebbawi F
    4. Lorenzon R
    5. Bellier B
    6. Rosenzwajg M
    7. Klatzmann D

    (2015) Human and Mouse CD8(+)CD25(+)FOXP3(+) Regulatory T Cells at Steady State and during Interleukin-2 Therapy

    Frontiers in Immunology 6:171.

    https://doi.org/10.3389/fimmu.2015.00171

    • PubMed
    • Google Scholar
21. 1. Clifford AJ
    2. Rincon G
    3. Owens JE
    4. Medrano JF
    5. Moshfegh AJ
    6. Baer DJ
    7. Novotny JA

    (2013) Single nucleotide polymorphisms in CETP, SLC46A1, SLC19A1, CD36, BCMO1, APOA5, and ABCA1 are significant predictors of plasma HDL in healthy adults

    Lipids in Health and Disease 12:66.

    https://doi.org/10.1186/1476-511X-12-66

    • PubMed
    • Google Scholar
22. 1. Coronel J
    2. Pinos I
    3. Amengual J

    (2019) β-carotene in obesity research: technical considerations and current status of the field

    Nutrients 11:842.

    https://doi.org/10.3390/nu11040842

    • PubMed
    • Google Scholar
23. 1. Coronel J
    2. Yu J
    3. Pilli N
    4. Kane MA
    5. Amengual J

    (2022) The conversion of β-carotene to vitamin A in adipocytes drives the anti-obesogenic effects of β-carotene in mice

    Molecular Metabolism 66:101640.

    https://doi.org/10.1016/j.molmet.2022.101640

    • PubMed
    • Google Scholar
24. 1. Couper KN
    2. Blount DG
    3. de Souza JB
    4. Suffia I
    5. Belkaid Y
    6. Riley EM

    (2007) Incomplete depletion and rapid regeneration of Foxp3+ regulatory T cells following anti-CD25 treatment in malaria-infected mice

    Journal of Immunology 178:4136–4146.

    https://doi.org/10.4049/jimmunol.178.7.4136

    • PubMed
    • Google Scholar
25. 1. Elias KM
    2. Laurence A
    3. Davidson TS
    4. Stephens G
    5. Kanno Y
    6. Shevach EM
    7. O’Shea JJ

    (2008) Retinoic acid inhibits Th17 polarization and enhances FoxP3 expression through a Stat-3/Stat-5 independent signaling pathway

    Blood 111:1013–1020.

    https://doi.org/10.1182/blood-2007-06-096438

    • PubMed
    • Google Scholar
26. 1. Emoto Y
    2. Wada H
    3. Okamoto H
    4. Kudo A
    5. Imai Y

    (2005) Retinoic acid-metabolizing enzyme Cyp26a1 is essential for determining territories of hindbrain and spinal cord in zebrafish

    Developmental Biology 278:415–427.

    https://doi.org/10.1016/j.ydbio.2004.11.023

    • PubMed
    • Google Scholar
27. 1. Felipe F
    2. Bonet ML
    3. Ribot J
    4. Palou A

    (2004) Modulation of resistin expression by retinoic acid and vitamin A status

    Diabetes 53:882–889.

    https://doi.org/10.2337/diabetes.53.4.882

    • PubMed
    • Google Scholar
28. 1. Felipe F
    2. Mercader J
    3. Ribot J
    4. Palou A
    5. Bonet ML

    (2005) Effects of retinoic acid administration and dietary vitamin A supplementation on leptin expression in mice: lack of correlation with changes of adipose tissue mass and food intake

    Biochimica et Biophysica Acta 1740:258–265.

    https://doi.org/10.1016/j.bbadis.2004.11.014

    • PubMed
    • Google Scholar
29. 1. Foks AC
    2. Lichtman AH
    3. Kuiper J

    (2015) Treating atherosclerosis with regulatory T cells

    Arteriosclerosis, Thrombosis, and Vascular Biology 35:280–287.

    https://doi.org/10.1161/ATVBAHA.114.303568

    • PubMed
    • Google Scholar
30. 1. Fontenot JD
    2. Rasmussen JP
    3. Williams LM
    4. Dooley JL
    5. Farr AG
    6. Rudensky AY

    (2005) Regulatory T cell lineage specification by the forkhead transcription factor foxp3

    Immunity 22:329–341.

    https://doi.org/10.1016/j.immuni.2005.01.016

    • PubMed
    • Google Scholar
31. 1. Girgis NM
    2. Gundra UM
    3. Loke P

    (2013) Immune regulation during helminth infections

    PLOS Pathogens 9:e1003250.

    https://doi.org/10.1371/journal.ppat.1003250

    • PubMed
    • Google Scholar
32. 1. Girgis NM
    2. Gundra UM
    3. Ward LN
    4. Cabrera M
    5. Frevert U
    6. Loke P

    (2014) Ly6C(high) monocytes become alternatively activated macrophages in schistosome granulomas with help from CD4+ cells

    PLOS Pathogens 10:e1004080.

    https://doi.org/10.1371/journal.ppat.1004080

    • PubMed
    • Google Scholar
33. 1. Goldberg IJ
    2. Sharma G
    3. Fisher EA

    (2020) Atherosclerosis: making a u turn

    Annual Review of Medicine 71:191–201.

    https://doi.org/10.1146/annurev-med-042418-011108

    • PubMed
    • Google Scholar
34. 1. Granados N
    2. Amengual J
    3. Ribot J
    4. Musinovic H
    5. Ceresi E
    6. von Lintig J
    7. Palou A
    8. Bonet ML

    (2013) Vitamin A supplementation in early life affects later response to an obesogenic diet in rats

    International Journal of Obesity 37:1169–1176.

    https://doi.org/10.1038/ijo.2012.190

    • PubMed
    • Google Scholar
35. 1. Grune T
    2. Lietz G
    3. Palou A
    4. Ross AC
    5. Stahl W
    6. Tang G
    7. Thurnham D
    8. Yin S
    9. Biesalski HK

    (2010) Beta-carotene is an important vitamin A source for humans

    The Journal of Nutrition 140:2268S–2285S.

    https://doi.org/10.3945/jn.109.119024

    • PubMed
    • Google Scholar
36. 1. Gundra UM
    2. Girgis NM
    3. Ruckerl D
    4. Jenkins S
    5. Ward LN
    6. Kurtz ZD
    7. Wiens KE
    8. Tang MS
    9. Basu-Roy U
    10. Mansukhani A
    11. Allen JE
    12. Loke P

    (2014) Alternatively activated macrophages derived from monocytes and tissue macrophages are phenotypically and functionally distinct

    Blood 123:e110–e122.

    https://doi.org/10.1182/blood-2013-08-520619

    • PubMed
    • Google Scholar
37. 1. Gundra UM
    2. Girgis NM
    3. Gonzalez MA
    4. San Tang M
    5. Van Der Zande HJP
    6. Lin J-D
    7. Ouimet M
    8. Ma LJ
    9. Poles J
    10. Vozhilla N
    11. Fisher EA
    12. Moore KJ
    13. Loke P

    (2017) Vitamin A mediates conversion of monocyte-derived macrophages into tissue-resident macrophages during alternative activation

    Nature Immunology 18:642–653.

    https://doi.org/10.1038/ni.3734

    • PubMed
    • Google Scholar
38. 1. Harari A
    2. Harats D
    3. Marko D
    4. Cohen H
    5. Barshack I
    6. Kamari Y
    7. Gonen A
    8. Gerber Y
    9. Ben-Amotz A
    10. Shaish A

    (2008) A 9-cis beta-carotene-enriched diet inhibits atherogenesis and fatty liver formation in LDL receptor knockout mice

    The Journal of Nutrition 138:1923–1930.

    https://doi.org/10.1093/jn/138.10.1923

    • PubMed
    • Google Scholar
39. 1. Haribhai D
    2. Lin W
    3. Relland LM
    4. Truong N
    5. Williams CB
    6. Chatila TA

    (2007) Regulatory T cells dynamically control the primary immune response to foreign antigen

    Journal of Immunology 178:2961–2972.

    https://doi.org/10.4049/jimmunol.178.5.2961

    • PubMed
    • Google Scholar
40. 1. Hayes ET
    2. Hagan CE
    3. Khoryati L
    4. Gavin MA
    5. Campbell DJ

    (2020) Regulatory T cells maintain selective access to IL-2 and Immune homeostasis despite substantially reduced CD25 function

    Journal of Immunology 205:2667–2678.

    https://doi.org/10.4049/jimmunol.1901520

    • PubMed
    • Google Scholar
41. 1. He L
    2. Jhong J-H
    3. Chen Q
    4. Huang K-Y
    5. Strittmatter K
    6. Kreuzer J
    7. DeRan M
    8. Wu X
    9. Lee T-Y
    10. Slavov N
    11. Haas W
    12. Marneros AG

    (2021) Global characterization of macrophage polarization mechanisms and identification of M2-type polarization inhibitors

    Cell Reports 37:109955.

    https://doi.org/10.1016/j.celrep.2021.109955

    • PubMed
    • Google Scholar
42. 1. Hessel S
    2. Eichinger A
    3. Isken A
    4. Amengual J
    5. Hunzelmann S
    6. Hoeller U
    7. Elste V
    8. Hunziker W
    9. Goralczyk R
    10. Oberhauser V
    11. von Lintig J
    12. Wyss A

    (2007) CMO1 deficiency abolishes vitamin A production from beta-carotene and alters lipid metabolism in mice

    The Journal of Biological Chemistry 282:33553–33561.

    https://doi.org/10.1074/jbc.M706763200

    • PubMed
    • Google Scholar
43. 1. Hori S
    2. Nomura T
    3. Sakaguchi S

    (2003) Control of regulatory T cell development by the transcription factor Foxp3

    Science 299:1057–1061.

    https://doi.org/10.1126/science.1079490

    • PubMed
    • Google Scholar
44. 1. Huang J
    2. Weinstein SJ
    3. Yu K
    4. Männistö S
    5. Albanes D

    (2018) Serum beta carotene and overall and cause-specific mortality

    Circulation Research 123:1339–1349.

    https://doi.org/10.1161/CIRCRESAHA.118.313409

    • PubMed
    • Google Scholar
45. 1. Josefs T
    2. Barrett TJ
    3. Brown EJ
    4. Quezada A
    5. Wu X
    6. Voisin M
    7. Amengual J
    8. Fisher EA

    (2020) Neutrophil extracellular traps promote macrophage inflammation and impair atherosclerosis resolution in diabetic mice

    JCI Insight 5:e134796.

    https://doi.org/10.1172/jci.insight.134796

    • PubMed
    • Google Scholar
46. 1. Josefs T
    2. Basu D
    3. Vaisar T
    4. Arets B
    5. Kanter JE
    6. Huggins L-A
    7. Hu Y
    8. Liu J
    9. Clouet-Foraison N
    10. Heinecke JW
    11. Bornfeldt KE
    12. Goldberg IJ
    13. Fisher EA

    (2021) Atherosclerosis regression and cholesterol efflux in hypertriglyceridemic mice

    Circulation Research 128:690–705.

    https://doi.org/10.1161/CIRCRESAHA.120.317458

    • PubMed
    • Google Scholar
47. 1. Kane MA
    2. Folias AE
    3. Wang C
    4. Napoli JL

    (2008) Quantitative profiling of endogenous retinoic acid in vivo and in vitro by tandem mass spectrometry

    Analytical Chemistry 80:1702–1708.

    https://doi.org/10.1021/ac702030f

    • PubMed
    • Google Scholar
48. 1. Kim JM
    2. Rasmussen JP
    3. Rudensky AY

    (2007) Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice

    Nature Immunology 8:191–197.

    https://doi.org/10.1038/ni1428

    • PubMed
    • Google Scholar
49. 1. Krivospitskaya O
    2. Elmabsout AA
    3. Sundman E
    4. Söderström LA
    5. Ovchinnikova O
    6. Gidlöf AC
    7. Scherbak N
    8. Norata GD
    9. Samnegård A
    10. Törmä H
    11. Abdel-Halim SM
    12. Jansson JH
    13. Eriksson P
    14. Sirsjö A
    15. Olofsson PS

    (2012) A CYP26B1 polymorphism enhances retinoic acid catabolism and may aggravate atherosclerosis

    Molecular Medicine 18:712–718.

    https://doi.org/10.2119/molmed.2012.00094

    • PubMed
    • Google Scholar
50. 1. León-Reyes G
    2. Rivera-Paredez B
    3. Hidalgo-Bravo A
    4. Flores YN
    5. Salmerón J
    6. Velázquez-Cruz R

    (2022) Common variant rs6564851 near the beta-carotene oxygenase 1 gene is associated with plasma triglycerides levels in middle-aged Mexican men adults

    Nutrition Research 103:30–39.

    https://doi.org/10.1016/j.nutres.2022.03.008

    • PubMed
    • Google Scholar
51. 1. Libby P
    2. Aikawa M

    (2002) Stabilization of atherosclerotic plaques: new mechanisms and clinical targets

    Nature Medicine 8:1257–1262.

    https://doi.org/10.1038/nm1102-1257

    • PubMed
    • Google Scholar
52. 1. Lietz G
    2. Oxley A
    3. Leung W
    4. Hesketh J

    (2012) Single nucleotide polymorphisms upstream from the β-carotene 15,15’-monoxygenase gene influence provitamin A conversion efficiency in female volunteers

    The Journal of Nutrition 142:161S–5S.

    https://doi.org/10.3945/jn.111.140756

    • PubMed
    • Google Scholar
53. 1. Lobo GP
    2. Amengual J
    3. Li HNM
    4. Golczak M
    5. Bonet ML
    6. Palczewski K
    7. von Lintig J

    (2010) Beta,beta-carotene decreases peroxisome proliferator receptor gamma activity and reduces lipid storage capacity of adipocytes in a beta,beta-carotene oxygenase 1-dependent manner

    The Journal of Biological Chemistry 285:27891–27899.

    https://doi.org/10.1074/jbc.M110.132571

    • PubMed
    • Google Scholar
54. 1. Lobo GP
    2. Amengual J
    3. Baus D
    4. Shivdasani RA
    5. Taylor D
    6. von Lintig J

    (2013) Genetics and diet regulate vitamin A production via the homeobox transcription factor ISX

    The Journal of Biological Chemistry 288:9017–9027.

    https://doi.org/10.1074/jbc.M112.444240

    • PubMed
    • Google Scholar
55. 1. Mercader J
    2. Ribot J
    3. Murano I
    4. Felipe F
    5. Cinti S
    6. Bonet ML
    7. Palou A

    (2006) Remodeling of white adipose tissue after retinoic acid administration in mice

    Endocrinology 147:5325–5332.

    https://doi.org/10.1210/en.2006-0760

    • PubMed
    • Google Scholar
56. 1. Miller AP
    2. Coronel J
    3. Amengual J

    (2020) The role of β-carotene and vitamin A in atherogenesis: evidences from preclinical and clinical studies

    Biochimica et Biophysica Acta. Molecular and Cell Biology of Lipids 1865:158635.

    https://doi.org/10.1016/j.bbalip.2020.158635

    • PubMed
    • Google Scholar
57. 1. Moore KJ
    2. Koplev S
    3. Fisher EA
    4. Tabas I
    5. Björkegren JLM
    6. Doran AC
    7. Kovacic JC

    (2018) Macrophage trafficking, inflammatory resolution, and genomics in atherosclerosis: JACC Macrophage in CVD Series (Part 2)

    Journal of the American College of Cardiology 72:2181–2197.

    https://doi.org/10.1016/j.jacc.2018.08.2147

    • PubMed
    • Google Scholar
58. 1. Moran NE
    2. Thomas-Ahner JM
    3. Fleming JL
    4. McElroy JP
    5. Mehl R
    6. Grainger EM
    7. Riedl KM
    8. Toland AE
    9. Schwartz SJ
    10. Clinton SK

    (2019) Single nucleotide polymorphisms in β-Carotene oxygenase 1 are associated with plasma lycopene responses to a tomato-soy juice intervention in men with prostate cancer

    The Journal of Nutrition 149:381–397.

    https://doi.org/10.1093/jn/nxy304

    • PubMed
    • Google Scholar
59. 1. Mucida D
    2. Park Y
    3. Kim G
    4. Turovskaya O
    5. Scott I
    6. Kronenberg M
    7. Cheroutre H

    (2007) Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid

    Science 317:256–260.

    https://doi.org/10.1126/science.1145697

    • PubMed
    • Google Scholar
60. 1. Murray PJ
    2. Allen JE
    3. Biswas SK
    4. Fisher EA
    5. Gilroy DW
    6. Goerdt S
    7. Gordon S
    8. Hamilton JA
    9. Ivashkiv LB
    10. Lawrence T
    11. Locati M
    12. Mantovani A
    13. Martinez FO
    14. Mege J-L
    15. Mosser DM
    16. Natoli G
    17. Saeij JP
    18. Schultze JL
    19. Shirey KA
    20. Sica A
    21. Suttles J
    22. Udalova I
    23. van Ginderachter JA
    24. Vogel SN
    25. Wynn TA

    (2014) Macrophage activation and polarization: nomenclature and experimental guidelines

    Immunity 41:14–20.

    https://doi.org/10.1016/j.immuni.2014.06.008

    • PubMed
    • Google Scholar
61. 1. Newby A
    2. George S
    3. Ismail Y
    4. Johnson J
    5. Sala-Newby G
    6. Thomas A

    (2009) Vulnerable atherosclerotic plaque metalloproteinases and foam cell phenotypes

    Thrombosis and Haemostasis 101:1006–1011.

    https://doi.org/10.1160/TH08-07-0469

    • Google Scholar
62. 1. O’Byrne SM
    2. Wongsiriroj N
    3. Libien J
    4. Vogel S
    5. Goldberg IJ
    6. Baehr W
    7. Palczewski K
    8. Blaner WS

    (2005) Retinoid absorption and storage is impaired in mice lacking lecithin:retinol acyltransferase (LRAT)

    The Journal of Biological Chemistry 280:35647–35657.

    https://doi.org/10.1074/jbc.M507924200

    • PubMed
    • Google Scholar
63. 1. Ohue Y
    2. Nishikawa H

    (2019) Regulatory T (Treg) cells in cancer: Can Treg cells be a new therapeutic target?

    Cancer Science 110:2080–2089.

    https://doi.org/10.1111/cas.14069

    • PubMed
    • Google Scholar
64. 1. Onda M
    2. Kobayashi K
    3. Pastan I

    (2019) Depletion of regulatory T cells in tumors with an anti-CD25 immunotoxin induces CD8 T cell-mediated systemic antitumor immunity

    PNAS 116:4575–4582.

    https://doi.org/10.1073/pnas.1820388116

    • PubMed
    • Google Scholar
65. 1. Ouimet M
    2. Ediriweera HN
    3. Gundra UM
    4. Sheedy FJ
    5. Ramkhelawon B
    6. Hutchison SB
    7. Rinehold K
    8. van Solingen C
    9. Fullerton MD
    10. Cecchini K
    11. Rayner KJ
    12. Steinberg GR
    13. Zamore PD
    14. Fisher EA
    15. Loke P
    16. Moore KJ

    (2015) MicroRNA-33-dependent regulation of macrophage metabolism directs immune cell polarization in atherosclerosis

    The Journal of Clinical Investigation 125:4334–4348.

    https://doi.org/10.1172/JCI81676

    • PubMed
    • Google Scholar
66. 1. Pinos I
    2. Yu J
    3. Pilli N
    4. Kane MA
    5. Amengual J

    (2023) Functional characterization of interleukin 4 and retinoic acid signaling crosstalk during alternative macrophage activation

    Biochimica et Biophysica Acta. Molecular and Cell Biology of Lipids 1868:159291.

    https://doi.org/10.1016/j.bbalip.2023.159291

    • PubMed
    • Google Scholar
67. 1. Puigserver P
    2. Vázquez F
    3. Bonet ML
    4. Picó C
    5. Palou A

    (1996) In vitro and in vivo induction of brown adipocyte uncoupling protein (thermogenin) by retinoic acid

    The Biochemical Journal 317 (Pt 3):827–833.

    https://doi.org/10.1042/bj3170827

    • PubMed
    • Google Scholar
68. 1. Quadro L
    2. Blaner WS
    3. Salchow DJ
    4. Vogel S
    5. Piantedosi R
    6. Gouras P
    7. Freeman S
    8. Cosma MP
    9. Colantuoni V
    10. Gottesman ME

    (1999) Impaired retinal function and vitamin A availability in mice lacking retinol-binding protein

    The EMBO Journal 18:4633–4644.

    https://doi.org/10.1093/emboj/18.17.4633

    • PubMed
    • Google Scholar
69. 1. Reboul E

    (2019) Mechanisms of carotenoid intestinal absorption: where do we stand?

    Nutrients 11:838.

    https://doi.org/10.3390/nu11040838

    • PubMed
    • Google Scholar
70. 1. Relevy NZ
    2. Harats D
    3. Harari A
    4. Ben-Amotz A
    5. Bitzur R
    6. Rühl R
    7. Shaish A

    (2015) Vitamin A-deficient diet accelerated atherogenesis in apolipoprotein E(-/-) mice and dietary β-carotene prevents this consequence

    BioMed Research International 2015:758723.

    https://doi.org/10.1155/2015/758723

    • PubMed
    • Google Scholar
71. 1. Rodriguez-Concepcion M
    2. Avalos J
    3. Bonet ML
    4. Boronat A
    5. Gomez-Gomez L
    6. Hornero-Mendez D
    7. Limon MC
    8. Meléndez-Martínez AJ
    9. Olmedilla-Alonso B
    10. Palou A
    11. Ribot J
    12. Rodrigo MJ
    13. Zacarias L
    14. Zhu C

    (2018) A global perspective on carotenoids: Metabolism, biotechnology, and benefits for nutrition and health

    Progress in Lipid Research 70:62–93.

    https://doi.org/10.1016/j.plipres.2018.04.004

    • PubMed
    • Google Scholar
72. 1. Ross AC
    2. Zolfaghari R

    (2011) Cytochrome P450s in the regulation of cellular retinoic acid metabolism

    Annual Review of Nutrition 31:65–87.

    https://doi.org/10.1146/annurev-nutr-072610-145127

    • PubMed
    • Google Scholar
73. 1. Seino Y
    2. Miki T
    3. Kiyonari H
    4. Abe T
    5. Fujimoto W
    6. Kimura K
    7. Takeuchi A
    8. Takahashi Y
    9. Oiso Y
    10. Iwanaga T
    11. Seino S

    (2008) Isx participates in the maintenance of vitamin A metabolism by regulation of beta-carotene 15,15’-monooxygenase (Bcmo1) expression

    The Journal of Biological Chemistry 283:4905–4911.

    https://doi.org/10.1074/jbc.M707928200

    • PubMed
    • Google Scholar
74. 1. Shaish A
    2. Daugherty A
    3. O’Sullivan F
    4. Schonfeld G
    5. Heinecke JW

    (1995) Beta-carotene inhibits atherosclerosis in hypercholesterolemic rabbits

    The Journal of Clinical Investigation 96:2075–2082.

    https://doi.org/10.1172/JCI118256

    • PubMed
    • Google Scholar
75. 1. Sharma M
    2. Schlegel MP
    3. Afonso MS
    4. Brown EJ
    5. Rahman K
    6. Weinstock A
    7. Sansbury BE
    8. Corr EM
    9. van Solingen C
    10. Koelwyn GJ
    11. Shanley LC
    12. Beckett L
    13. Peled D
    14. Lafaille JJ
    15. Spite M
    16. Loke P
    17. Fisher EA
    18. Moore KJ

    (2020) Regulatory T cells license macrophage pro-resolving functions during atherosclerosis regression

    Circulation Research 127:335–353.

    https://doi.org/10.1161/CIRCRESAHA.119.316461

    • PubMed
    • Google Scholar
76. 1. Soehnlein O
    2. Libby P

    (2021) Targeting inflammation in atherosclerosis - from experimental insights to the clinic

    Nature Reviews. Drug Discovery 20:589–610.

    https://doi.org/10.1038/s41573-021-00198-1

    • PubMed
    • Google Scholar
77. 1. Szondi DC
    2. Wong JK
    3. Vardy LA
    4. Cruickshank SM

    (2021) Arginase signalling as a key player in chronic wound pathophysiology and healing

    Frontiers in Molecular Biosciences 8:773866.

    https://doi.org/10.3389/fmolb.2021.773866

    • PubMed
    • Google Scholar
78. 1. von Lintig J
    2. Vogt K

    (2000) Filling the gap in vitamin A research: molecular identification of an enzyme cleaving beta-carotene to retinal

    The Journal of Biological Chemistry 275:11915–11920.

    https://doi.org/10.1074/jbc.275.16.11915

    • PubMed
    • Google Scholar
79. 1. Wang Y
    2. Chung S-J
    3. McCullough ML
    4. Song WO
    5. Fernandez ML
    6. Koo SI
    7. Chun OK

    (2014) Dietary carotenoids are associated with cardiovascular disease risk biomarkers mediated by serum carotenoid concentrations

    The Journal of Nutrition 144:1067–1074.

    https://doi.org/10.3945/jn.113.184317

    • PubMed
    • Google Scholar
80. 1. Weinstock A
    2. Fisher EA

    (2019) Methods to study monocyte and macrophage trafficking in atherosclerosis progression and resolution

    Methods in Molecular Biology 1951:153–165.

    https://doi.org/10.1007/978-1-4939-9130-3_12

    • PubMed
    • Google Scholar
81. 1. Wing K
    2. Ekmark A
    3. Karlsson H
    4. Rudin A
    5. Suri-Payer E

    (2002) Characterization of human CD25+ CD4+ T cells in thymus, cord and adult blood

    Immunology 106:190–199.

    https://doi.org/10.1046/j.1365-2567.2002.01412.x

    • PubMed
    • Google Scholar
82. 1. Witztum JL
    2. Lichtman AH

    (2014) The influence of innate and adaptive immune responses on atherosclerosis

    Annual Review of Pathology 9:73–102.

    https://doi.org/10.1146/annurev-pathol-020712-163936

    • PubMed
    • Google Scholar
83. 1. Yabuta S
    2. Urata M
    3. Wai Kun RY
    4. Masaki M
    5. Shidoji Y

    (2016) Common SNP rs6564851 in the BCO1 Gene Affects the Circulating Levels of β-Carotene and the Daily Intake of Carotenoids in Healthy Japanese Women

    PLOS ONE 11:e0168857.

    https://doi.org/10.1371/journal.pone.0168857

    • PubMed
    • Google Scholar
84. 1. Yu M
    2. Amengual J
    3. Menon A
    4. Kamaly N
    5. Zhou F
    6. Xu X
    7. Saw PE
    8. Lee S-J
    9. Si K
    10. Ortega CA
    11. Choi WI
    12. Lee I-H
    13. Bdour Y
    14. Shi J
    15. Mahmoudi M
    16. Jon S
    17. Fisher EA
    18. Farokhzad OC

    (2017) Targeted Nanotherapeutics Encapsulating Liver X Receptor Agonist GW3965 Enhance Antiatherogenic Effects without Adverse Effects on Hepatic Lipid Metabolism in Ldlr^-/- Mice

    Advanced Healthcare Materials 6:20.

    https://doi.org/10.1002/adhm.201700313

    • PubMed
    • Google Scholar
85. 1. Yurdagul A Jr
    2. Subramanian M
    3. Wang X
    4. Crown SB
    5. Ilkayeva OR
    6. Darville L
    7. Kolluru GK
    8. Rymond CC
    9. Gerlach BD
    10. Zheng Z
    11. Kuriakose G
    12. Kevil CG
    13. Koomen JM
    14. Cleveland JL
    15. Muoio DM
    16. Tabas I

    (2020) Macrophage metabolism of apoptotic cell-derived arginine promotes continual efferocytosis and resolution of Injury

    Cell Metabolism 31:518–533.

    https://doi.org/10.1016/j.cmet.2020.01.001

    • PubMed
    • Google Scholar
86. 1. Zhou F
    2. Wu X
    3. Pinos I
    4. Abraham BM
    5. Barrett TJ
    6. von Lintig J
    7. Fisher EA
    8. Amengual J

    (2020) β-Carotene conversion to vitamin A delays atherosclerosis progression by decreasing hepatic lipid secretion in mice

    Journal of Lipid Research 61:1491–1503.

    https://doi.org/10.1194/jlr.RA120001066

    • PubMed
    • Google Scholar

Author details

1. Ivan Pinos

   Division of Nutritional Sciences, University of Illinois Urbana Champaign, Urbana, United States

   Contribution

   Data curation, Formal analysis, Investigation, Methodology, Project administration

   Contributed equally with

   Johana Coronel and Asma'a Albakri

   Competing interests

   No competing interests declared

2. Johana Coronel

   Department of Food Science and Human Nutrition, University of Illinois Urbana Champaign, Urbana, United States

   Contribution

   Data curation, Formal analysis, Investigation, Methodology, Project administration

   Contributed equally with

   Ivan Pinos and Asma'a Albakri

   Competing interests

   No competing interests declared

3. Asma'a Albakri

   Division of Nutritional Sciences, University of Illinois Urbana Champaign, Urbana, United States

   Contribution

   Data curation, Formal analysis, Investigation, Methodology, Writing - original draft

   Contributed equally with

   Ivan Pinos and Johana Coronel

   Competing interests

   No competing interests declared

4. Amparo Blanco

   Division of Nutritional Sciences, University of Illinois Urbana Champaign, Urbana, United States

   Contribution

   Data curation, Formal analysis, Validation, Investigation, Visualization, Methodology, Project administration, Writing – review and editing

   Competing interests

   No competing interests declared

5. Patrick McQueen

   Division of Nutritional Sciences, University of Illinois Urbana Champaign, Urbana, United States

   Contribution

   Data curation, Formal analysis, Investigation, Methodology, Writing - original draft

   Competing interests

   No competing interests declared

6. Donald Molina

   Department of Food Science and Human Nutrition, University of Illinois Urbana Champaign, Urbana, United States

   Contribution

   Methodology

   Competing interests

   No competing interests declared

7. JaeYoung Sim

   Department of Food Science and Human Nutrition, University of Illinois Urbana Champaign, Urbana, United States

   Contribution

   Methodology

   Competing interests

   No competing interests declared

8. Edward A Fisher

   The Leon H. Charney Division of Cardiology, Department of Medicine, The Marc and Ruti Bell Program in Vascular Biology, New York University Grossman School of Medicine, NYU Langone Medical Center, New York, United States

   Contribution

   Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-9802-143X

9. Jaume Amengual

   1. Division of Nutritional Sciences, University of Illinois Urbana Champaign, Urbana, United States
   2. Department of Food Science and Human Nutrition, University of Illinois Urbana Champaign, Urbana, United States

   Contribution

   Conceptualization, Resources, Data curation, Supervision, Funding acquisition, Validation, Investigation, Methodology, Writing - original draft, Project administration, Writing – review and editing

   For correspondence

   jaume6@illinois.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-6077-3545

• 919

  views

• 102

  downloads

• 0

  citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.