Epithelial retinoic acid receptor β regulates serum amyloid A expression and vitamin A-dependent intestinal immunity

Gattu, Sureka; Bang, Ye Ji; Pendse, Mihir; Dende, Chaitanya; Chara, Andrew L.; Harris, Tamia A.; Wang, Yuhao; Ruhn, Kelly A.; Kuang, Zheng; Sockanathan, Shanthini; Hooper, Lora V.

doi:10.1073/pnas.1812069116

Cited by 44 publications

(37 citation statements)

References 32 publications

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“…The retinoic acid synthesized by epithelial cells, while available to underlying immune cells, is also capable of initiating a signaling response within IECs themselves. Retinoic acid signaling in intestinal epithelial cells (IECs) regulates epithelial lineage specification and promotes small intestinal T helper 17 (Th17) responses [11, 12]. Dietary vitamin A deficiency markedly increases susceptibility to enteric pathogens [13], however, relatively little is known about the contribution of IEC-intrinsic retinoic acid signaling in the context of infection.…”

Section: Introductionmentioning

confidence: 99%

Epithelium intrinsic vitamin A signaling co-ordinates pathogen clearance in the gut via IL-18

Iyer

Grizotte-Lake

Gordon

et al. 2019

Preprint

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AbstractIntestinal epithelial cells (IECs) are at the forefront of host-pathogen interactions, coordinating a cascade of immune responses to confer protection against pathogens. Here we show that IEC-intrinsic vitamin A signaling restricts pathogen invasion early in the infection and subsequently activates immune cells to promote pathogen clearance. Mice blocked for retinoic acid receptor (RAR) signaling selectively in IECs (stopΔIEC) showed significantly higher Salmonella burden in colonic tissues early in the infection associated with higher luminal and systemic loads of the pathogen at later stages. Higher susceptibility of stopΔIEC mice correlated with attenuated mucosal interferon gamma (IFNγ) production by underlying immune cells. We found that, at homeostasis, the intestinal epithelium of stopΔIEC mice produced significantly lower amounts of interleukin 18 (IL-18), a potent inducer of IFNγ. Regulation of IL-18 by vitamin A was also observed in a dietary model of vitamin A supplementation. IL-18 reconstitution in stopΔIEC mice restored resistance to Salmonella by promoting epithelial cell shedding to eliminate infected cells and limit pathogen invasion early in infection. Further, IL-18 augmented IFNγ production by underlying immune cells to restrict pathogen burden and systemic spread. Our work uncovers a critical role for vitamin A in coordinating a biphasic immune response to Salmonella infection by regulating IL-18 production by IECs.Author SummaryEpithelial cells line the intestinal lumen, forming a barrier between the body and dietary and microbial contents in the lumen. Apart from absorbing nutrients from diet, these epithelial cells help mediate a stable, symbiotic relationship between microbes in the gut and the immune cells. During infection, they help co-ordinate the immune response to counter the infection. How dietary micronutrients, such as vitamin A, inform epithelial cell function during infection is poorly understood. Using a model where epithelial cells in the gut cannot respond to vitamin A signals, we find that epithelial vitamin A signaling promotes resistance to Salmonella infection. We show that, vitamin A increases the production of a key cytokine, interleukin 18, by epithelial cells. IL-18 promotes shedding of infected epithelial cells to reduce the pathogen invasion while also inducing the production of interferon gamma by immune cells to mediate pathogen clearance. Thus, epithelial cells dynamically respond to dietary vitamin A to regulate interleukin 18 production and potentiate resistance to infection.

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Section: Introductionmentioning

confidence: 99%

Epithelium intrinsic vitamin A signaling co-ordinates pathogen clearance in the gut via IL-18

Iyer

Grizotte-Lake

Gordon

et al. 2019

Preprint

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“…TGF-β and TLA expression were normal in the IEC dnRAR GI tract. IEC have been shown to be required for the production of serum amyloid A (SAA) proteins that are hypothesized to deliver retinol to T cells and IEC important for GI immunity ( 45 ). It is possible that the IEC require functional RAR to induce SAA delivery of retinol for the RA mediated induction of CD8αα+ on TCRαβ+ T cells in the gut.…”

Section: Discussionmentioning

confidence: 99%

“…A limitation of the study is that protein levels for the tight junction proteins were not measured. Gattu et.al showed that A+ IEC dnRAR had normal barrier function ( 45 ). However, Salmonella infection of A+ IEC dnRAR mice resulted in more translocation of bacteria to the spleen and liver than in the WT littermates ( 45 ).…”

Section: Discussionmentioning

confidence: 99%

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Retinoid Signaling in Intestinal Epithelial Cells Is Essential for Early Survival From Gastrointestinal Infection

et al. 2020

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Vitamin A deficiency (A-) increases morbidity and mortality to gastrointestinal (GI) infection. Blocking retinoid signaling (dominant negative retinoic acid receptor, dnRAR) in intestinal epithelial cells (IEC, IEC dnRAR) had no effect on vitamin A absorption, the expression of tight junction proteins or the integrity of the barrier. Immune cells in the gut were present in normal frequencies in the IEC dnRAR mice, with the exception of the T cell receptor (TCR)αβ+/CD8αα cells, which were significantly lower than in wildtype littermates. Challenging the IEC dnRAR mice with dextran sodium sulfate to induce colitis or Citrobacter rodentium infection resulted in similar disease to wildtype littermates. Feeding mice vitamin A deficient diets reduced vitamin A status and the A-IEC dnRAR mice developed more severe colitis and C. rodentium infection. In particular, retinoid signaling in the IEC was crucial for the A-host to survive early infection following C. rodentium. Treating A-mice with retinoic acid (RA) beginning on the day of infection protects most mice from early lethality. However, RA treatment of the A-IEC dnRAR mice was ineffective for preventing lethality following C. rodentium infection. Retionid signaling in IEC is critical, especially when there are reduced levels of dietary vitamin A. IEC are direct targets of vitamin A for mounting early defense against infection.

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“…The retinoic acid synthesized by epithelial cells, while available to underlying immune cells, is also capable of initiating a signaling response within IECs themselves. Retinoic acid signaling in intestinal epithelial cells regulates epithelial lineage specification and promotes small intestinal T helper 17 (Th17) responses [11,12]. Dietary vitamin A deficiency markedly increases susceptibility to enteric pathogens [13], however, relatively little is known about the contribution of IEC-intrinsic retinoic acid signaling in the context of infection.…”

Section: Introductionmentioning

confidence: 99%

Epithelium intrinsic vitamin A signaling co-ordinates pathogen clearance in the gut via IL-18

et al. 2020

View full text Add to dashboard Cite

Intestinal epithelial cells (IECs) are at the forefront of host-pathogen interactions, coordinating a cascade of immune responses to protect against pathogens. Here we show that IECintrinsic vitamin A signaling restricts pathogen invasion early in the infection and subsequently activates immune cells to promote pathogen clearance. Mice blocked for retinoic acid receptor (RAR) signaling selectively in IECs (stop ΔIEC ) showed higher Salmonella burden in colonic tissues early in the infection that associated with higher luminal and systemic loads of the pathogen at later stages. Higher pathogen burden in stop ΔIEC mice correlated with attenuated mucosal interferon gamma (IFNγ) production by underlying immune cells. We found that, at homeostasis, the intestinal epithelium of stop ΔIEC mice produced significantly lower amounts of interleukin 18 (IL-18), a potent inducer of IFNγ. Regulation of IL-18 by vitamin A was also observed in a dietary model of vitamin A supplementation. IL-18 reconstitution in stop ΔIEC mice restored resistance to Salmonella by promoting epithelial cell shedding to eliminate infected cells and limit pathogen invasion early in infection. Further, IL-18 augmented IFNγ production by underlying immune cells to restrict pathogen burden and systemic spread. Our work uncovers a critical role for vitamin A in coordinating a biphasic immune response to Salmonella infection by regulating IL-18 production by IECs. Author summaryEpithelial cells line the intestinal lumen, forming a barrier between the body and dietary and microbial contents in the lumen. Apart from absorbing nutrients from diet, these epithelial cells help mediate a stable, symbiotic relationship between commensal bacteria and the immune cells. During infection, they help co-ordinate the immune response to counter the infection. How dietary micronutrients, such as vitamin A, inform epithelial cell function during infection is poorly understood. Using a model where epithelial cells in the gut cannot respond to vitamin A signals, we find that epithelial vitamin A signaling PLOS PATHOGENS PLOS Pathogens | https://doi.

show abstract

Epithelial retinoic acid receptor β regulates serum amyloid A expression and vitamin A-dependent intestinal immunity

Cited by 44 publications

References 32 publications

Epithelium intrinsic vitamin A signaling co-ordinates pathogen clearance in the gut via IL-18

Epithelium intrinsic vitamin A signaling co-ordinates pathogen clearance in the gut via IL-18

Retinoid Signaling in Intestinal Epithelial Cells Is Essential for Early Survival From Gastrointestinal Infection

Epithelium intrinsic vitamin A signaling co-ordinates pathogen clearance in the gut via IL-18

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