Research ArticleExperimental Studies
Open Access

A Novel Immunomodulatory Mechanism by Which Vitamin D Influences Folate Receptor 3 Expression to Reduce COVID-19 Severity

ROSY J. LU, PURUSHA SHIRVANI and MICHAEL F. HOLICK
Anticancer Research October 2022, 42 (10) 5043-5048; DOI: https://doi.org/10.21873/anticanres.16013

Abstract

Background/Aim: Identify potential mechanisms involving gene expression changes through which vitamin D supplementation could be beneficial in preventing adverse COVID-19 outcomes. Materials and Methods: We performed a literature review to identify differentially expressed genes (DEGs) in the blood between severe and mild COVID-19 patients. We compared these with the top DEGs induced by 6 months of 10,000 IU/day vitamin D supplementation in healthy adults who were vitamin D deficient/insufficient. We used bioinformatic tools to look for a vitamin D response element (VDRE) in DEGs. Results: FOLR3, RGS1, GPR84, and LRRN3 were the most significantly altered genes by 6 months of 10,000 IU/day vitamin D supplementation whose expression levels were also involved in COVID-19 severity. FOLR3 and GPR84 were found to be consistently up-regulated and RGS1 and LRRN3 consistently down-regulated in severe COVID-19 infection. FOLR3 and LRRN3 were down-regulated and RGS1 and GPR84 were up-regulated by 10,000 IU/day vitamin D supplementation. Conclusion: FOLR3 and RGS1 are expressed in neutrophils and lymphocytes, respectively. Vitamin D supplementation may decrease the neutrophil-lymphocyte ratio as has been reported in patients admitted with severe symptoms. There is evidence that vitamin D directly influences the expression of the RGS1 gene through vitamin D receptor binding. A potential negative VDRE (nVDRE) in an intron of the FOLR3 gene was found, which was homologous with two known nVDREs. Combined with other transcription factor elements near the newly identified nVDRE, these observations may explain the mechanism by which vitamin D regulates these genes, thus influencing COVID-19 outcomes.

Key Words:

Vitamin D deficiency has also been associated with a variety of medical conditions, including cardiovascular disease, autoimmune diseases, type 2 diabetes, and cancers (1). Vitamin D sufficiency is defined as having a serum concentration of 25-hydroxyvitamin D (25(OH)D), the major circulating form of vitamin D, greater than 30 ng/ml (1). The COVID-19 pandemic has been a cause of devastating mortality worldwide. However, a previous study has found that vitamin D sufficient individuals had a 54% decrease in COVID-19 infection compared to vitamin D deficient individuals (2). Previous studies have also suggested that vitamin D sufficiency correlates with a reduced risk of COVID-19 severity and mortality (3, 4). Nevertheless, approximately 70% of the United States population has been found to be either vitamin D deficient or insufficient (5). Therefore, vitamin D supplementation could potentially be a simple and inexpensive way to reduce the risk of the healthy population developing adverse COVID-19 outcomes.

While there have been many clinical trials investigating the effect of vitamin D supplementation on COVID-19 prognosis, there have been few studies examining the molecular pathways through which vitamin D supplementation may reduce risk of COVID-19 severity, particularly through gene expression. A previous study has found that 6 months of 10,000 IU/day vitamin D supplementation for deficient and insufficient individuals induced gene expression changes in peripheral white blood cells (6). The study observed 1,289 differentially expressed genes, including 800 up-regulated and 489 down-regulated genes (6).

This analysis aims to compare transcriptional changes resulting from severe COVID-19 and vitamin D supplementation in order to identify potential mechanisms involving changes in gene expression through which vitamin D supplementation could be beneficial in preventing adverse COVID-19 outcomes.

Materials and Methods

We used the dataset of differentially expressed genes (DEGs) in the white blood cells of initially vitamin D deficient or insufficient healthy adults [serum 25(OH)D concentration < 30 ng/ml] who received 6 months of 600, 4,000, or 10,000 IU/day vitamin D supplementation compiled by Shirvani et al. (6). The top 10 up-regulated and down-regulated DEGs (all have p-value<0.05) in adults receiving 6 months of 10,000 IU/day vitamin D supplementation were the focus of our literature search (Table I and Table II). We searched for studies in the PubMed database through July 2022 identifying differentially expressed genes (DEGs) in white blood cells involved in COVID-19 severity, and compared them to the top 10 up-regulated and down-regulated DEGs by 10,000 IU/day vitamin D supplementation. We compared a sequence of candidate VDREs with known VDREs to identify a VDRE in the FOLR3 gene. We also searched for other transcription factor elements to confirm VDRE functionality.

View this table:
Table I.

Top 10 up-regulated differentially expressed genes in adults receiving six months of 10,000 IU/day vitamin D supplementation.

View this table:
Table II.

Top 10 down-regulated differentially expressed genes in adults receiving six months of 10,000 IU/day vitamin D supplementation.

Results

Studies on blood cell gene expression profile influencing COVID-19 severity. We identified in the literature search that FOLR3, RGS1, GPR84, and LRRN3 were genes whose expression was significantly altered (|fold change| >2, p-value <0.05) between severe and mild COVID-19 patients (7-9). TNFAIP3, SLED1, HILPDA, JUN, IGIP, WLS, and ZNF594, which were also part of the top 10 up-regulated and top 10 down-regulated genes by 6 months of 10,000 IU/day vitamin D supplementation, were found by some studies to be differentially expressed in blood cells between severe and mild COVID-19 patients, although not by others (9, 10).

Differential expression of FOLR3. FOLR3 (folate receptor 3) expression was consistently found to be up-regulated (fold change >2, p-value <0.05) in blood cells of severe COVID-19 patients compared to mild COVID-19 patients (7-9). A study also found FOLR3 expression to be up-regulated (fold change >2, p-value <0.05) in the whole blood transcriptomes of clinical COVID-19 patients compared to individuals with entirely asymptomatic COVID-19 (11). In contrast, Vitamin D supplementation down-regulated FOLR3 expression in a dose-dependent manner (fold change=−1.0, −1.7, and −2.7 for the 600, 4,000, and 10,000 IU/day supplementation groups, respectively; p-value <0.05 for the 4,000 and 10,000 IU/day groups) (6). We also found a potential negative VDRE (nVDRE) in an intron of the FOLR3 gene that was homologous with two known nVDREs. There were also other transcription factor elements near the newly identified nVDRE. All of these may indicate a causal relationship between vitamin D supplementation and FOLR3 expression. Therefore, FOLR3 could be a gene of interest involving vitamin D’s effect on COVID-19 outcomes, as its dose-dependent down-regulation by vitamin D supplementation in white blood cells could counter its up-regulation of expression with increasing COVID-19 severity (Figure 1). Long-term vitamin D supplementation for deficient and insufficient adults could potentially reduce the risk of developing severe COVID-19 through a mechanism associated with the down-regulation of FOLR3 gene expression in the white blood cells.

Figure 1.
Figure 1.

FOLR3 expression was down-regulated with vitamin D supplementation in a dose-dependent manner (fold change=−1.0, −1.7, and −2.7 for the 600, 4,000, and 10,000 IU/day supplementation groups, respectively). FOLR3 expression was up-regulated in severe COVID-19 patients compared to mild COVID-19 patients (average fold change=5.4). *p-Value <0.05.

Other genes. RGS1 (regulator of G-protein signaling 1) was consistently found to be down-regulated (fold change <−2, p-value <0.05) in the blood cells of severe COVID-19 patients compared to mild COVID-19 patients (8, 9). Conversely, 6 months of 10,000 IU/day vitamin D supplementation significantly up-regulated RGS1 expression (fold change=4.2, p-value <0.05). Interestingly, the up-regulation of RGS1 by vitamin D supplementation was not dose-dependent; 6 months of 600 and 4,000 IU/day vitamin D supplementation was found to down-regulate RGS1 (fold change=−2.1 and −1.6, respectively, p-value <0.05). There is evidence to show that vitamin D directly influences expression of the RGS1 gene through vitamin D receptor binding (12).

GPR84 (G protein-coupled receptor 84) was consistently found to be up-regulated (fold change >2, p-value <0.05) in blood cells of severe COVID-19 patients compared to mild COVID-19 patients (8, 9). GPR84 had been also found to be up-regulated (fold change >2, p-value <0.05) by 6 months of 10,000 IU/day vitamin D supplementation (6). LRRN3, a gene down-regulated by 6 months of 10,000 IU/day vitamin D supplementation (6), was also consistently found to be down-regulated (fold change <−2, p-value <0.05) in blood cells in severe COVID-19 compared to mild COVID-19 (8, 9).

Discussion

Vitamin D supplementation & decreased neutrophil-lymphocyte ratio. The FOLR3 gene encodes the folate receptor gamma protein, a soluble secretory protein released from neutrophil granulocytes as part of the innate immune response (13). The RGS1 gene encodes the regulator of G-protein signaling 1 protein, which is not expressed in neutrophils, but highly expressed in various types of lymphocytes, including natural killer cells and T cells (14). Hence, a decreased FOLR3 and increased RGS1 expression level observed in the group that received 6 months of 10,000 IU/day vitamin D supplementation could modulate the immune system by decreasing neutrophil count and increasing lymphocyte count. A high neutrophil-lymphocyte ratio on patient admission has been found to predict COVID-19 severity and mortality (15). Therefore, decreasing the neutrophil-lymphocyte ratio could be a mechanism through which vitamin D supplementation reduces the risk of adverse COVID-19 outcomes (Figure 2). This is consistent with clinical findings that oral 25(OH)D3 treatment correcting vitamin D deficiency/insufficiency was associated with a significant decrease in neutrophil-lymphocyte ratio in COVID-19 patients (16).

Figure 2.
Figure 2.

Changes in the immune system associated with vitamin D supplementation. Vitamin D sufficiency has been found to decrease the ratio of neutrophils compared to lymphocytes, which would lead to improved COVID-19 outcomes, as well as explain the observed decrease in FOLR3 mRNA transcript levels and increase in RGS1 transcript levels in the blood.

Direct effect of active form of vitamin D on FOLR3 expression. Vitamin D supplementation could also have an effect on COVID-19 outcomes by directly suppressing FOLR3 expression. The active form of vitamin D, 1,25-dihydroxyvitamin D [1,25(OH)2D], has been found to directly affect the expression of over 1000 genes in most tissues and cell types via activating the nuclear transcription factor vitamin D receptor (VDR) (1, 17). The VDR and the enzyme 25-hydroxyvitamin D-1α-hydroxylase (CYP27B1), which metabolizes 25(OH)D to 1,25(OH)2D, are expressed in several immune cell types, including macrophages, activated monocytes, neutrophils and T lymphocytes (1, 18). Therefore, increased levels of circulating 25(OH)D could lead to increased local production of its active metabolite 1,25(OH)2D in white blood cells. The active form of vitamin D [1,25(OH)2D] could then potentially bind with its nuclear vitamin D receptor (VDR), creating a complex that would bind to a vitamin D response element (VDRE) on the target genes. The potential vitamin D response element on the FOLR3 gene may explain the mechanism by which vitamin D regulates FOLR3 in immune cells. The potential FOLR3 VDRE is homologous to known negative VDRE sequences in other genes. This could be a mechanism through which 1,25(OH)2D directly represses FOLR3 expression. The vitamin D receptor (VDR) has been shown to compete with NFAT for DNA binding to regulate NFAT’s target genes (19, 20). Therefore, 1,25(OH)2D may indirectly down-regulate expression of FOLR3 through VDR competing with NFAT for DNA binding sites in the FOLR3 gene (Figure 3).

Figure 3.
Figure 3.

Possible direct repression of FOLR3 expression by the 1,25(OH)2D-bound vitamin D receptor (VDR). We hypothesize that increased 25(OH)D levels increase immune cells’ local production of the active form of vitamin D [1,25(OH)2D], which may bind to its nuclear receptor on an NFAT transcription factor binding site in the FOLR3 promoter, thus inhibiting the formation of the NFAT complex necessary for FOLR3 transcription.

It has been hypothesized that upon secretion, the FOLR3 protein binds to 5- methyltetrahydrofolate (5-methylTHF), which deprives cells of this natural folate (13). 5-methylTHF is required for the methyl group transfer in converting homocysteine to methionine (21). A lack of 5-methylTHF would lead to an excess of homocysteine, which has been shown to induce neutrophil extracellular trap (NET) formation (22). NETs have been found to be a major cause of the immunothrombosis, organ damage, and acute respiratory distress syndrome (ARDS) associated with COVID-19 morbidity and mortality (23). Therefore, direct inhibition of FOLR3 expression by vitamin D supplementation could play a role in reducing severe COVID-19 by reducing NET formation.

COVID-19 is not the only disease associated with increased expression of the FOLR3 gene. FOLR3 has been found to be over-expressed in autoimmune diseases, such as rheumatoid arthritis and psoriasis (24), cardiovascular diseases, such as coronary artery disease (25), various cancers (26), and Alzheimer’s disease and mild cognitive impairment (27). Therefore, decreasing FOLR3 expression could be a way through which being vitamin D sufficient with a 25(OH)D of at least 30 ng/ml has a protective effect against other diseases as well. Indeed, considering how 10,000 IU/day of vitamin D supplementation decreased FOLR3 expression nearly trifold but severe COVID-19 raised it five-fold, further studies should be conducted to determine the effects of higher than 10,000 IU/day of vitamin D supplementation on FOLR3 expression to potentially reduce severity of COVID-19 in at-risk patients.

Acknowledgements

The Authors are grateful to Boston University’s RISE Internship program for offering the opportunity and connecting RJL to complete a research project in the Vitamin D, Skin and Bone Research Laboratory. RJL is also thankful for the support of her fellow RISE interns Ramneek Kaur and Aashi Mittal, and everyone who has made this an enjoyable & insightful experience.

Footnotes

  • Authors’ Contributions

    M.F. Holick designed the project. R.J. Lu performed the literature search and analyzed the data. P. Shirvani completed the vitamin D response element (VDRE) evaluation. R.J. Lu, P. Shirvani, and M.F. Holick drafted the manuscript. M.F. Holick provided final approval.

  • Conflicts of Interest

    Michael F. Holick has served as a consultant for Biogena Inc., Ontometrics Inc. and Solius Inc, and has grants from Carbogen Amcis BV and Solius Inc. The Authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

  • Received July 30, 2022.
  • Revision received August 25, 2022.
  • Accepted August 26, 2022.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

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