Immune Response: Investigating the role of vitamin D in asthma
Results in mice suggest that vitamin D reduces the symptoms of asthma by controlling an immune response that leads to inflammation of the airways.
- Department of Biology, Ashoka University, India
- Simons Ashoka Fellowship Program, Trivedi School of Biosciences, Ashoka University, India
- Koita Centre for Digital Health, Trivedi School of Biosciences, Ashoka University, India
Vitamin D deficiency has burgeoned into a major public health concern, exacerbated by dietary habits and pollution among other factors (Cui et al., 2023). While vitamin D is well known to be important for maintaining healthy bones, it has also been linked with various immune disorders, including asthma.
Supplements of vitamin D are being increasingly used to treat immune-related conditions. However, it remains unclear precisely how vitamin D is able to improve the outcome of these disorders (Scragg, 2018). Now, in eLife, Scott Weiss, Ardu Halu and co-workers – including Ayşe Kiliç as joint first author with Halu – report how vitamin D regulates an immune response that is a major contributor to asthma (Kiliç et al., 2023).
First, the team – who are based at Brigham and Women’s Hospital and Harvard Medical School, and institutes in Germany, Japan, Russia, and the United States – revisited the findings of a clinical trial called the Vitamin D Antenatal Asthma Reduction Trial (VDAART). In the trial, pregnant women who had a history of Asthma or allergies (or whose partner, the other biological parent, had a similar history), were given low or high doses of vitamin D during pregnancy. Analyses of the data found that higher vitamin D supplementation did not significantly reduce asthma in the offspring (Litonjua et al., 2016; Litonjua et al., 2020). However, a more nuanced reanalysis – which adjusted for baseline vitamin D levels to account for factors such as dietary intake – reported a reduced risk of asthma in the offspring of women who received a higher dose of vitamin D during pregnancy (Wolsk et al., 2017).
Kiliç et al. set out to find the genetic underpinnings of this protective effect, focusing their attention on chromosome 17, which contains regions strongly associated with asthma and other immune diseases (Bansal et al., 2021). Across chromosome 17 are sites where the receptor for vitamin D (known as VDR) can bind. Bioinformatic analysis revealed that some of these VDR binding sites overlapped with genetic variants associated with diseases triggered by the immune response mediated by T helper type 2 cells. These immune cells (known as Th2 for short) are a subset of white blood cells which respond proactively to invading pathogens like helminths, as well as recurrent exposures. Th2 cells act by producing inflammatory mediators as well as by modulating the activity of other cells in the immune system. They are also activated by allergens, such as mites and pollens, which can lead to allergic inflammation and disorders like asthma.
A detailed exploration of these overlapping regions suggested that VDR can trigger a cascade that regulates genes involved in the Th2 immune response. This genetic regulation could either promote or repress the Th2 response, depending on other genetic variants present in the proximity.
With a hypothesis established, the researchers tested their findings in mice which had been exposed to extracts from house dust mites to mimic the asthma phenotype (Figure 1A). They found that mice deficient in vitamin D or lacking VDRs displayed a more severe phenotype. Further experiments revealed that house dust mite exposure also caused the Th2 cells to express higher levels of VDR. When these Th2 cells were exposed to calcitriol (the active form of vitamin D), the VDRs bound to the calcitriol and migrated from the cytosol into the nucleus (Figure 1B).
Figure 1
The vitamin D receptor and its role in inflammation of the airways.
(A) To mimic the symptoms of asthma, Kiliç et al. treated a lab-grown strain of mice (known as C57Bl/6) with extracts from house dust mites (HDM). This activated a group of immune cells called T helper type 2 (Th2; green) in the lungs of the mice, leading to inflammation of their airways. (B) Kiliç et al. found that exposure to dust mites also caused the Th2 cells to produce more vitamin D receptors (purple). When the cells were treated with calcitriol, the active form of vitamin D (blue circles with black lines), the receptors migrated from the cytosol to the nucleus. Once there, the receptor can regulate the expression of genes involved in the Th2 response, including the gene Ikzf3 which suppresses the inflammatory response triggered by Th2 cells.
© 2024, BioRender Inc. Figure 1 was created using BioRender.com, and is published under a CC BY-NC-ND license. Further reproductions must adhere to the terms of this license.
These findings suggest that VDR acts like a lock waiting for its key. Access to the key (vitamin D), and migration of the VDR into the nucleus, possibly unlocks the transcriptional regulation required to modulate the immune pathways. Furthermore, VDR expression was contingent upon baseline vitamin D levels, suggesting that this vitamin has both a preventive and therapeutic potential. Kiliç et al. also found that one of the genes that VDR regulates (called Ikzf3) is a major factor in suppressing the Th2 immune response (Figure 1B). This effect is likely mediated through the STAT signaling axis, which is a critical pathway regulating inflammation (Hu et al., 2021).
The study by Kiliç, Halu, Weiss and colleagues sheds light on how vitamin D offers protective benefits against asthma. However, several pathophysiological pathways can lead to the characteristic airway inflammation associated with asthma (Moore and Bleecker, 2014). Subgroup analysis during clinical trials, along with targeted exploration of relevant biomarkers, could help identify who would benefit most from vitamin D supplements. The latest findings also underscore the importance of vitamin D in a wider sense, as the Th2 response is associated with several other chronic inflammatory diseases.
That being said, it is essential to be mindful of the broader biological role of vitamin D, as it influences both the innate and the adaptive immune system via a number of different cell types (Colotta et al., 2017). This complexity may be why scientific literature on vitamin D is marred by contradictory findings: for instance, a previous study has even shown loss of VDR to be protective against asthma (Wittke et al., 2004). However, this complexity should not deter researchers from trying to develop a deeper mechanistic understanding of vitamin D effects. Such an understanding could, in the future, enable personalized treatment strategies for individuals with immune disorders such as asthma.
References
-
Advances in asthma geneticsAdvances in Genetics 107:1–32.https://doi.org/10.1016/bs.adgen.2020.11.001
-
Modulation of inflammatory and immune responses by vitamin DJournal of Autoimmunity 85:78–97.https://doi.org/10.1016/j.jaut.2017.07.007
-
The JAK/STAT signaling pathway: from bench to clinicSignal Transduction and Targeted Therapy 6:402.https://doi.org/10.1038/s41392-021-00791-1
-
Six-year follow-up of a trial of antenatal vitamin D for asthma reductionThe New England Journal of Medicine 382:525–533.https://doi.org/10.1056/NEJMoa1906137
-
Asthma heterogeneity and severity-why is comprehensive phenotyping important?Lancet Respiratory Medicine 2:10–11.https://doi.org/10.1016/S2213-2600(13)70288-1
-
Limitations of vitamin D supplementation trials: Why observational studies will continue to help determine the role of vitamin D in healthThe Journal of Steroid Biochemistry and Molecular Biology 177:6–9.https://doi.org/10.1016/j.jsbmb.2017.06.006
-
Vitamin D receptor-deficient mice fail to develop experimental allergic asthmaJournal of Immunology 173:3432–3436.https://doi.org/10.4049/jimmunol.173.5.3432
-
Vitamin D supplementation in pregnancy, prenatal 25(OH)D levels, race, and subsequent asthma or recurrent wheeze in offspring: Secondary analyses from the Vitamin D Antenatal Asthma Reduction TrialThe Journal of Allergy and Clinical Immunology 140:1423–1429.https://doi.org/10.1016/j.jaci.2017.01.013
Article and author information
Author details
Publication history
Copyright
© 2024, Sharma and Garg
This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 632
- views
-
- 60
- downloads
-
- 1
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Immune Response: Investigating the role of vitamin D in asthma
eLife 13:e97031.
https://doi.org/10.7554/eLife.97031
Further reading
-
- Genetics and Genomics
Osteoporosis, characterized by reduced bone density and strength, increases fracture risk, pain, and limits mobility. Established therapies of parathyroid hormone (PTH) analogs effectively promote bone formation and reduce fractures in severe osteoporosis, but their use is limited by potential adverse effects. In the pursuit of safer osteoporosis treatments, we investigated R25CPTH, a PTH variant wherein the native arginine at position 25 is substituted by cysteine. These studies were prompted by our finding of high bone mineral density in a hypoparathyroidism patient with the R25C homozygous mutation, and we explored its effects on PTH type-1 receptor (PTH1R) signaling in cells and bone metabolism in mice. Our findings indicate that R25CPTH(1–84) forms dimers both intracellularly and extracellularly, and the synthetic dimeric peptide, R25CPTH(1–34), exhibits altered activity in PTH1R-mediated cyclic AMP (cAMP) response. Upon a single injection in mice, dimeric R25CPTH(1–34) induced acute calcemic and phosphaturic responses comparable to PTH(1–34). Furthermore, repeated daily injections increased calvarial bone thickness in intact mice and improved trabecular and cortical bone parameters in ovariectomized (OVX) mice, akin to PTH(1–34). The overall results reveal a capacity of a dimeric PTH peptide ligand to activate the PTH1R in vitro and in vivo as PTH, suggesting a potential path of therapeutic PTH analog development.
-
- Developmental Biology
- Genetics and Genomics
Asthenoteratozoospermia, a prevalent cause of male infertility, lacks a well-defined etiology. DNAH12 is a special dynein featured by the absence of a microtubule-binding domain, however, its functions in spermatogenesis remain largely unknown. Through comprehensive genetic analyses involving whole-exome sequencing and subsequent Sanger sequencing on infertile patients and fertile controls from six distinct families, we unveiled six biallelic mutations in DNAH12 that co-segregate recessively with male infertility in the studied families. Transmission electron microscopy (TEM) revealed pronounced axonemal abnormalities, including inner dynein arms (IDAs) impairment and central pair (CP) loss in sperm flagella of the patients. Mouse models (Dnah12-/- and Dnah12mut/mut) were generated and recapitulated the reproductive defects in the patients. Noteworthy, DNAH12 deficiency did not show effects on cilium organization and function. Mechanistically, DNAH12 was confirmed to interact with two other IDA components DNALI1 and DNAH1, while disruption of DNAH12 leads to failed recruitment of DNALI1 and DNAH1 to IDAs and compromised sperm development. Furthermore, DNAH12 also interacts with radial spoke head proteins RSPH1, RSPH9, and DNAJB13 to regulate CP stability. Moreover, the infertility of Dnah12-/- mice could be overcome by intracytoplasmic sperm injection (ICSI) treatment. Collectively, DNAH12 plays a crucial role in the proper organization of axoneme in sperm flagella, but not cilia, by recruiting DNAH1 and DNALI1 in both humans and mice. These findings expand our comprehension of dynein component assembly in flagella and cilia and provide a valuable marker for genetic counseling and diagnosis of asthenoteratozoospermia in clinical practice.
