Epithelial Histone Deacetylase 3 Instructs Intestinal Immunity by Coordinating Local Lymphocyte Activation

Navabi, Nazanin; Whitt, Jordan; Wu, Shu-en; Woo, Vivienne; Moncivaiz, Jessica; Jordan, Michael B.; Vallance, Bruce A.; Way, Sing Sing; Alenghat, Theresa

doi:10.1016/j.celrep.2017.04.046

Cited by 40 publications

(40 citation statements)

References 52 publications

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“…These results suggest that epithelial RAR signaling modulates the mucosal IFNγ response via IL-18 to mediate resistance to pathogen. These results align with a study where epithelial IL-18 expression, regulated by histone deacetylase 3 activity, primes IFNγ response in intraepithelial lymphocytes to restrict colonization by Citrobacter [45]. IL-18 induction by protozoan colonization in the gut exerts a similar protective effects against Salmonella by promoting mucosal Th1 and Th17 response [46].…”

Section: Resultssupporting

confidence: 88%

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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: Resultssupporting

confidence: 88%

“…IL-18 and IFNγ are implicated in a host of gastrointestinal and systemic infections caused Toxoplasmas gondii [60], C. rodentium [45], Listeria monocytogenes [61, 62] among others. These pathogens represent a diversity of adhesion/invasion strategies as well as potential for systemic spread and toxicity.…”

Section: Discussionmentioning

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

View full text Add to dashboard Cite

show abstract

“…These results suggest that epithelial RAR signaling modulates the mucosal IFNγ response via IL-18 to mediate resistance to pathogen. Our results align with a previous study where epithelial IL-18 expression, regulated by histone deacetylase 3 activity, primes IFNγ response in intraepithelial lymphocytes to restrict colonization by Citrobacter [51]. IL-18 induction by protozoan colonization in the gut…”

Section: Intestinal Epithelium-intrinsic Rar Signaling Regulates Pathsupporting

confidence: 92%

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

et al. 2020

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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.

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“…For example, microbiota-derived short-chain fatty acids have been shown to promote histone crotonylation in the colon via histone deacetylases 44 . In addition, epithelial-specific deletion of HDAC3 results in increased susceptibility to Citrobacter rodentium in association with impaired IFN-γ production by CD8 + intraepithelial lymphocytes 45 . Our findings of reduced histone H3Ac in the absence of microbiota in early life further underscores the relationship between the microbiota and epigenetic modification in the intestine.…”

Section: Discussionmentioning

confidence: 99%

Erythroid differentiation regulator-1 induced by microbiota in early life drives intestinal stem cell proliferation and regeneration

et al. 2020

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Gut microbiota and their metabolites are instrumental in regulating intestinal homeostasis. However, early-life microbiota associated influences on intestinal development remain incompletely understood. Here we demonstrate that co-housing of germ-free (GF) mice with specific-pathogen free (SPF) mice at weaning (exGF) results in altered intestinal gene expression. Our results reveal that one highly differentially expressed gene, erythroid differentiation regulator-1 (Erdr1), is induced during development in SPF but not GF or exGF mice and localizes to Lgr5 + stem cells and transit amplifying (TA) cells. Erdr1 functions to induce Wnt signaling in epithelial cells, increase Lgr5 + stem cell expansion, and promote intestinal organoid growth. Additionally, Erdr1 accelerates scratch-wound closure in vitro, increases Lgr5 + intestinal stem cell regeneration following radiation-induced injury in vivo, and enhances recovery from dextran sodium sulfate (DSS)-induced colonic damage. Collectively, our findings indicate that early-life microbiota controls Erdr1-mediated intestinal epithelial proliferation and regeneration in response to mucosal damage.

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Epithelial Histone Deacetylase 3 Instructs Intestinal Immunity by Coordinating Local Lymphocyte Activation

Cited by 40 publications

References 52 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

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

Erythroid differentiation regulator-1 induced by microbiota in early life drives intestinal stem cell proliferation and regeneration

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