Vitamin A Impairs the Reprogramming of Tregs into IL-17-Producing Cells during Intestinal Inflammation

Tejón, Gabriela; Manrı́quez, V.; Calisto, Jaime De; Flores-Santibáñez, Felipe; Hidalgo, Yessia; Crisóstomo, Natalia; Fernández, Dominique; Sauma, Daniela; Mora, J. Rodrigo; Bono, Marı́a Rosa; Rosemblatt, Mario

doi:10.1155/2015/137893

Cited by 40 publications

(26 citation statements)

References 40 publications

(43 reference statements)

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“…Blimp1 is an established marker of effector Treg cells, required for their full functionality(107). The upregulation of this gene in the colon in the VAS condition is in line with the literature that VA is required for Treg development and function(5,(108)(109)(110)(111)(112).…”

supporting

confidence: 73%

RNAseq studies reveal distinct transcriptional response to vitamin A deficiency in small intestine versus colon, uncovering novel vitamin A-regulated genes

Chai¹,

Lyu²,

Chen³

et al. 2019

Preprint

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Vitamin A (VA) deficiency remains prevalent in resource limited countries, affecting over 250 million preschool aged children. Vitamin A deficiency is associated with reduced 2 intestinal barrier function and increased risk of mortality due to mucosal infection. Citrobacter rodentium (C. rodentium) infection in mice is a model for diarrheal diseases in humans. During C. rodentium infection, vitamin A deficient (VAD) mice displayed reduced survival rate and pathogen clearance compared to their vitamin A sufficient (VAS) counterparts. Objectives: To characterize and compare the impact of vitamin A (VA) deficiency on gene expression patterns in the small intestine (SI) and the colon, and to discover novel target genes in VA-related biological pathways. Methods: vitamin A deficient (VAD) mice were generated by feeding VAD diet to pregnant C57/BL6 dams and their post-weaning offspring. Total mRNA extracted from SI and colon were sequenced using Illumina HiSeq 2500 platform. Differentially Expressed Gene (DEG), Gene Ontology (GO) enrichment, and Weighted Gene Co-expression Network Analysis (WGCNA) were performed to characterize expression patterns and co-expression patterns. Results:The comparison between VAS and VAD groups detected 49 and 94 DEGs in SI and colon, respectively. According to GO information, DEGs in the SI demonstrated significant enrichment in categories relevant to retinoid metabolic process, molecule binding, and immune function. Immunity related pathways, such as "humoral immune response" and "complement activation," were positively associated with VA in SI. On the contrary, in colon, "cell division" was the only enriched category and was negatively associated with VA. Three co-expression modules showed significant correlation with VA status in SI and were identified as modules of interest. Those modules contained four known retinoic acid targets. Therefore we have prioritized the other module members (e.g. Mbl2, Mmp9, Cxcl14, and Nr0b2) to be investigated as candidate genes regulated by VA. Also in SI, markers of two cell types, Mast cell and Tuft cell, were found altered by VA status. Comparison of co-expression modules between SI and colon indicated distinct regulatory networks in these two organs. Material and MethodsAnimals. C57BL/6 mice, originally purchased from Jackson Laboratories (Bar Harbor, MN), were bred and maintained at the Pennsylvania State University (University Park, PA) for experiments. Mice were exposed to a 12 hour light, 12 hour dark cycle with ad libitum access to food and water. All animal experiments were performed according to the Pennsylvania State University's Institutional Animal Care and Use Committee (IACUC) guideline (IACUC # 43445). Vitamin A deficient (VAD) and vitamin A sufficient (VAS) mice were generated as previously described (23,(27)(28)(29). Briefly, VAS or VAD diets were fed to pregnant mothers and the weanlings. VAS diet contained 25 μg of retinyl acetate per day whereas VAD diet did not contain any VA. At weaning, mice were maintained on their respective d...

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supporting

confidence: 73%

RNAseq studies reveal distinct transcriptional response to vitamin A deficiency in small intestine versus colon, uncovering novel vitamin A-regulated genes

Chai¹,

Lyu²,

Chen³

et al. 2019

Preprint

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“…RA, together with TGFβ, promotes naïve CD4 + to become Foxp3 + Tregs and RA alone has also inhibitory effects on Th17 cell differentiation (Figure 3 ). Others have also described that VitA can impair the reprogramming of Tregs into IL-17-producing cells during intestinal inflammation ( 214 ).…”

Section: Nutrients and Their Impact On Microbiota And Immune Responsementioning

confidence: 99%

The Impact of Western Diet and Nutrients on the Microbiota and Immune Response at Mucosal Interfaces

et al. 2017

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Recent findings point toward diet having a major impact on human health. Diets can either affect the gut microbiota resulting in alterations in the host’s physiological responses or by directly targeting the host response. The microbial community in the mammalian gut is a complex and dynamic system crucial for the development and maturation of both systemic and mucosal immune responses. Therefore, the complex interaction between available nutrients, the microbiota, and the immune system are central regulators in maintaining homeostasis and fighting against invading pathogens at mucosal sites. Westernized diet, defined as high dietary intake of saturated fats and sucrose and low intake of fiber, represent a growing health risk contributing to the increased occurrence of metabolic diseases, e.g., diabetes and obesity in countries adapting a westernized lifestyle. Inflammatory bowel diseases (IBD) and asthma are chronic mucosal inflammatory conditions of unknown etiology with increasing prevalence worldwide. These conditions have a multifactorial etiology including genetic factors, environmental factors, and dysregulated immune responses. Their increased prevalence cannot solely be attributed to genetic considerations implying that other factors such as diet can be a major contributor. Recent reports indicate that the gut microbiota and modifications thereof, due to a consumption of a diet high in saturated fats and low in fibers, can trigger factors regulating the development and/or progression of both conditions. While asthma is a disease of the airways, increasing evidence indicates a link between the gut and airways in disease development. Herein, we provide a comprehensive review on the impact of westernized diet and associated nutrients on immune cell responses and the microbiota and how these can influence the pathology of IBD and asthma.

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“…Retinoids have been used as anti‐inflammatory drugs in the treatment of inflammatory diseases such as psoriasis, acne, cutaneous lupus erythematosus, colitis, encephalomyelitis, and systemic lupus erythematosus . The clinical effects may be related to effects by retinoids on immune cell functions . Oral administration of retinoids can decrease experimentally induced arthritis in rats, including the loss of juxta‐articular bone .…”

Section: Introductionmentioning

confidence: 99%

Effects of retinoids on physiologic and inflammatory osteoclastogenesis in vitro

Lionikaite

Westerlund

Conaway

et al. 2018

Journal of Leukocyte Biology

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Increased intake of vitamin A (retinoids) is associated with decreased bone mass and increased fracture risk in humans. Mechanistic studies in rodents have shown that hypervitaminosis A results in decreased bone mass caused by an increase in periosteal osteoclasts while simultaneously decreasing endocortic osteoclasts. In vivo and ex vivo bone organ cultures have demonstrated that excess retinoids increase osteoclast formation due to increased receptor activator of nuclear factor kappa B-ligand (RANKL) expression. In vitro, studies using murine bone marrow macrophages (BMM) have shown that retinoids inhibit osteoclast formation induced by recombinant RANKL. These opposing in vivo/ex vivo versus in vitro effects may elucidate why excess retinoids affect periosteal and endocortic osteoclast formation differently. In addition, it has been reported that retinoids can inhibit osteoclast formation under inflammatory conditions such as experimentally induced arthritis in mice. In the present study, we have compared the effect of all-trans-retinoic acid (ATRA) on physiologically and inflammatory induced osteoclastogenesis. ATRA inhibited physiologically induced (RANKL) osteoclast formation of human peripheral blood monocytes and mouse BMM as well as human monocytes stimulated with the pro-inflammatory compounds, TNF-α and LPS. The inhibition was due to impeded differentiation, rather than fusion, of mononucleated progenitor cells. ATRA disrupted differentiation by interfering with osteoclastogenic intracellular signaling. In line with this view, overexpression of Tnfrsf11a (encodes for RANK) in BMM could not overcome the inhibition of osteoclastogenesis by ATRA. The data suggest that ATRA inhibits both physiologic and inflammatory osteoclast differentiation of progenitors from the bone marrow and peripheral blood.

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Vitamin A Impairs the Reprogramming of Tregs into IL-17-Producing Cells during Intestinal Inflammation

Cited by 40 publications

References 40 publications

RNAseq studies reveal distinct transcriptional response to vitamin A deficiency in small intestine versus colon, uncovering novel vitamin A-regulated genes

RNAseq studies reveal distinct transcriptional response to vitamin A deficiency in small intestine versus colon, uncovering novel vitamin A-regulated genes

The Impact of Western Diet and Nutrients on the Microbiota and Immune Response at Mucosal Interfaces

Effects of retinoids on physiologic and inflammatory osteoclastogenesis in vitro

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