title: Dietary cholesterol directly induces acute inflammasome-dependent intestinal inflammation.
abstract: Prolonged ingestion of a cholesterol- or saturated fatty acid-enriched diet induces chronic, often systemic, auto-inflammatory responses resulting in significant health problems worldwide. In vivo information regarding the local and direct inflammatory effect of these dietary components in the intestine and, in particular, on the intestinal epithelium is lacking. Here we report that both mice and zebrafish exposed to high-fat (HFDs) or high-cholesterol (HCDs) diets develop acute innate inflammatory responses within hours, reflected in the localized interleukin-1β-dependent accumulation of myeloid cells in the intestine. Acute HCD-induced intestinal inflammation is dependent on cholesterol uptake via Niemann-Pick C1-like 1 and inflammasome activation involving apoptosis-associated Speck-like protein containing a caspase recruitment domain, which leads to Caspase-1 activity in intestinal epithelial cells. Extended exposure to HCD results in localized, inflammation-dependent, functional dysregulation as well as systemic pathologies. Our model suggests that dietary cholesterol initiates intestinal inflammation in epithelial cells.
authors.affiliation: Department of Life Sciences, Faculty of Natural Sciences, Imperial College London, Sir Alexander Fleming Building, London SW7 2AZ, UK.
authors.forename: Fränze
authors.initials: F
authors.lastname: Progatzky
authors.affiliation: Department of Life Sciences, Faculty of Natural Sciences, Imperial College London, Sir Alexander Fleming Building, London SW7 2AZ, UK.
authors.forename: Navjyot J
authors.initials: NJ
authors.lastname: Sangha
authors.affiliation: Department of Life Sciences, Faculty of Natural Sciences, Imperial College London, Sir Alexander Fleming Building, London SW7 2AZ, UK.
authors.forename: Nagisa
authors.initials: N
authors.lastname: Yoshida
authors.affiliation: Department of Life Sciences, Faculty of Natural Sciences, Imperial College London, Sir Alexander Fleming Building, London SW7 2AZ, UK.
authors.forename: Marie
authors.initials: M
authors.lastname: McBrien
authors.affiliation: Department of Life Sciences, Faculty of Natural Sciences, Imperial College London, Sir Alexander Fleming Building, London SW7 2AZ, UK.
authors.forename: Jackie
authors.initials: J
authors.lastname: Cheung
authors.affiliation: 1] Department of Life Sciences, Faculty of Natural Sciences, Imperial College London, Sir Alexander Fleming Building, London SW7 2AZ, UK [2] National Heart and Lung Institute, Imperial College London, London W12 0NN, UK.
authors.forename: Alice
authors.initials: A
authors.lastname: Shia
authors.affiliation: National Heart and Lung Institute, Imperial College London, London W12 0NN, UK.
authors.forename: James
authors.initials: J
authors.lastname: Scott
authors.affiliation: 1] Computational and Systems Medicine, Faculty of Medicine, Department of Surgery and Cancer, Imperial College London, London SW7 2AZ, UK [2] Section of Hepatology, Imperial College London, Norfolk Place, London W2 1NY, UK [3] Centre for Digestive and Gut Health, Imperial College London, London W2 1NY, UK [4] School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3AX, UK.
authors.forename: Julian R
authors.initials: JR
authors.lastname: Marchesi
authors.affiliation: Department of Life Sciences, Faculty of Natural Sciences, Imperial College London, Sir Alexander Fleming Building, London SW7 2AZ, UK.
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Lamb
authors.affiliation: Department of Life Sciences, Faculty of Natural Sciences, Imperial College London, Sir Alexander Fleming Building, London SW7 2AZ, UK.
authors.forename: Laurence
authors.initials: L
authors.lastname: Bugeon
authors.affiliation: Department of Life Sciences, Faculty of Natural Sciences, Imperial College London, Sir Alexander Fleming Building, London SW7 2AZ, UK.
authors.forename: Margaret J
authors.initials: MJ
authors.lastname: Dallman
mesh_terms: D000818:Animals; D001583:Benzoxazoles / Q000494:pharmacology; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology; D020170:Caspase 1 / Q000235:genetics / Q000276:immunology; D002791:Cholesterol, Dietary / Q000009:adverse effects*; D059305:Diet, High-Fat; D005227:Fatty Acids / Q000378:metabolism; D005234:Fatty Liver / Q000209:etiology* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D005260:Female; D007113:Immunity, Innate; D058847:Inflammasomes / Q000187:drug effects; D007249:Inflammation / Q000209:etiology / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000378:metabolism; D007413:Intestinal Mucosa / Q000276:immunology* / Q000473:pathology; D007422:Intestines / Q000276:immunology / Q000473:pathology; D026901:Membrane Transport Proteins / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D022423:Myeloid Cells / Q000276:immunology / Q000473:pathology; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D014230:Triazoles / Q000494:pharmacology; D015027:Zebrafish
chemical_list: C511179:3-benzyl-7-(2-benzoxazolyl)thio-1,2,3-triazolo(4,5-d)pyrimidine; D001583:Benzoxazoles; D002352:Carrier Proteins; D002791:Cholesterol, Dietary; D005227:Fatty Acids; D058847:Inflammasomes; D053583:Interleukin-1beta; D026901:Membrane Transport Proteins; D016328:NF-kappa B; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C482445:Npc1l1 protein, mouse; D014230:Triazoles; D020170:Caspase 1