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.

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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

   1. Division of Nutritional Sciences, University of Illinois Urbana Champaign, Urbana, United States
   2. The University of Jordan, School of Agriculture, Department of Nutrition and Food Technology, Amman, Jordan

   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

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