Dietary cholesterol directly induces acute inflammasome-dependent intestinal inflammation

• Published in: Nature communications 2014-12, Vol.5 (1), p.5864, Article 5864
• Main Authors: Progatzky, Fränze, Sangha, Navjyot J., Yoshida, Nagisa, McBrien, Marie, Cheung, Jackie, Shia, Alice, Scott, James, Marchesi, Julian R., Lamb, Jonathan R., Bugeon, Laurence, Dallman, Margaret J.
• Format: Article
• Language: English
• Subjects: 13/21; 13/31; 13/51; 13/89; 14/1; 14/19; 14/34; 14/35; 38/77; 64/116; 64/60; 692/420/2780; 692/699/249/2510/257; 692/700/2814; Animals; Benzoxazoles - pharmacology; Carrier Proteins - genetics; Carrier Proteins - immunology; Caspase 1 - genetics; Caspase 1 - immunology; Cholesterol, Dietary - adverse effects; Diet, High-Fat; Fatty Acids - metabolism; Fatty Liver - etiology; Fatty Liver - genetics; Fatty Liver - immunology; Fatty Liver - pathology; Female; Humanities and Social Sciences; Immunity, Innate; Inflammasomes - drug effects; Inflammation - etiology; Inflammation - genetics; Inflammation - immunology; Inflammation - pathology; Interleukin-1beta - biosynthesis; Interleukin-1beta - metabolism; Intestinal Mucosa - immunology; Intestinal Mucosa - pathology; Intestines - immunology; Intestines - pathology; Membrane Transport Proteins - genetics; Membrane Transport Proteins - immunology; Mice; Mice, Inbred BALB C; multidisciplinary; Myeloid Cells - immunology; Myeloid Cells - pathology; NF-kappa B - genetics; NF-kappa B - immunology; NLR Family, Pyrin Domain-Containing 3 Protein; Science; Science (multidisciplinary); Triazoles - pharmacology; Zebrafish
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms6864

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. Chronic consumption of a Western-type diet leads to systemic inflammation of undefined origin, which contributes to metabolic disease. Here Progatzky et al . identify an immediate early step in the process by showing that dietary cholesterol rapidly activates inflammasomes in the gut epithelium.