Dietary cholesterol directly induces acute inflammasome-dependent intestinal inflammation

Progatzky, Fränze; Sangha, Navjyot J.; Yoshida, Norimasa; McBrien, Marie; Cheung, Jackie L. Y.; Shia, Alice; Scott, James; Marchesi, Julian R.; Lamb, Jonathan R.; Bugeon, Laurence; Dallman, Margaret J.

doi:10.1038/ncomms6864

Cited by 95 publications

(112 citation statements)

References 54 publications

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“…Other studies in zebrafish larvae have also shown ASC and caspase A dependent effects during the response to inflammasome-associated stimuli including cholesterol induced gut inflammation (Progatzky et al , 2014), the response to viral infection (Varela et al , 2014), and tissue injury (Ogryzko et al , 2013). Using an ASC overexpression assay, we showed that ASC oligomerization increased only in response to Lm-pyro, but not to cytosolic bacteria alone.…”

Section: Discussionmentioning

confidence: 97%

Macrophages mediate flagellin induced inflammasome activation and host defense in zebrafish

Vincent

Freisinger

Lam

et al. 2015

Cellular Microbiology

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Summary The inflammasome is an innate immune complex whose rapid inflammatory outputs play a critical role in controlling infection, however the host cells that mediate inflammasome responses in vivo are not well defined. Using zebrafish larvae, we examined the cellular immune responses to inflammasome activation during infection. We compared the host responses to two Listeria monocytogenes strains: wild type and Lm-pyro, a strain engineered to activate the inflammasome via ectopic expression of flagellin. Infection with Lm-pyro led to activation of the inflammasome, macrophage pyroptosis, and ultimately attenuation of virulence. Depletion of caspase A, the zebrafish caspase-1 homolog, restored Lm-pyro virulence. Inflammasome activation specifically recruited macrophages to infection sites, whereas neutrophils were equally recruited to WT and Lm-pyro infections. Similar to caspase A depletion, macrophage deficiency rescued Lm-pyro virulence to wild type levels, while defective neutrophils had no specific effect. Neutrophils were however important for general clearance of L. monocytogenes, as both wild type and Lm-pyro were more virulent in larvae with defective neutrophils. This study characterizes a novel model for inflammasome studies in an intact host, establishes the importance of macrophages during inflammasome responses, and adds importance to the role of neutrophils in controlling L. monocytogenes infections.

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Section: Discussionmentioning

confidence: 97%

Macrophages mediate flagellin induced inflammasome activation and host defense in zebrafish

Vincent

Freisinger

Lam

et al. 2015

Cellular Microbiology

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“…2010, Kim et al . 2012, Progatzky et al . 2014) and, at least for high-fat diet, has been associated with a decrease in the Bacteroidetes -to- Firmicutes ratio (Kim et al .…”

Section: Discussionmentioning

confidence: 99%

11β-hydroxysteroid dehydrogenase-1 deficiency alters the gut microbiome response to Western diet

Johnson

Opiyo

Thomson

et al. 2017

Journal of Endocrinology

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The enzyme 11β-hydroxysteroid dehydrogenase (11β-HSD) interconverts active glucocorticoids and their intrinsically inert 11-keto forms. The type 1 isozyme, 11β-HSD1, predominantly reactivates glucocorticoids in vivo and can also metabolise bile acids. 11β-HSD1-deficient mice show altered inflammatory responses and are protected against the adverse metabolic effects of a high-fat diet. However, the impact of 11β-HSD1 on the composition of the gut microbiome has not previously been investigated. We used high-throughput 16S rDNA amplicon sequencing to characterise the gut microbiome of 11β-HSD1-deficient and C57Bl/6 control mice, fed either a standard chow diet or a cholesterol- and fat-enriched ‘Western’ diet. 11β-HSD1 deficiency significantly altered the composition of the gut microbiome, and did so in a diet-specific manner. On a Western diet, 11β-HSD1 deficiency increased the relative abundance of the family Bacteroidaceae, and on a chow diet, it altered relative abundance of the family Prevotellaceae. Our results demonstrate that (i) genetic effects on host–microbiome interactions can depend upon diet and (ii) that alterations in the composition of the gut microbiome may contribute to the aspects of the metabolic and/or inflammatory phenotype observed with 11β-HSD1 deficiency.

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“…Interestingly, cholesterol crystals were also recently demonstrated to function as direct innate immune ligands, inducing pro-inflammatory cytokine production via ligation of Mincle, a scavenger receptor with a cholesterol interaction motif [11]. In other settings, dietary cholesterol, internalized via the receptor Niemann-Pick C1-like 1, also activates the inflammasome and IL-1β production in intestinal epithelial cells in vivo [40]. …”

Section: Coupling Of Intracellular Sterols To Macrophage Innate Immunitymentioning

confidence: 99%

The Intracellular Cholesterol Landscape: Dynamic Integrator of the Immune Response

Fessler

2016

Trends in Immunology

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Cholesterol has typically been considered an exogenous, disease-related factor in immunity; however, recent literature suggests that a paradigm shift is in order. Sterols are now recognized to ligate several immune receptors. Altered flux through the mevalonic acid synthesis pathway also appears to be a required event in the antiviral interferon response of macrophages and in the activation, proliferation, and differentiation of T cells. In this review, evidence is discussed that suggests an intrinsic, ‘professional’ role for sterols and oxysterols in macrophage and T cell immunity. Host defense may have been the original selection pressure behind the development of mechanisms for intracellular cholesterol homeostasis. Functional coupling between sterol metabolism and immunity has fundamental implications for health and disease.

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Dietary cholesterol directly induces acute inflammasome-dependent intestinal inflammation

Cited by 95 publications

References 54 publications

Macrophages mediate flagellin induced inflammasome activation and host defense in zebrafish

Macrophages mediate flagellin induced inflammasome activation and host defense in zebrafish

11β-hydroxysteroid dehydrogenase-1 deficiency alters the gut microbiome response to Western diet

The Intracellular Cholesterol Landscape: Dynamic Integrator of the Immune Response

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