Acute High-Fat Diet Impairs Macrophage-Supported Intestinal Damage Resolution

Authors

Andrea A Hill
Myunghoo Kim
Daniel F Zegarra-Ruiz
Lin-Chun Chang
Kendra Norwood
Adrien Assié
Wan-Jung H Wu
Michael C Renfroe
Hyo Wong Song
Angela M Major
Buck S Samuel
Joseph M Hyser
Randy S Longman
Gretchen E Diehl

Publication Date

2-8-2023

Journal

JCI Insight

DOI

10.1172/jci.insight.164489

PMID

36538527

PMCID

PMC9977439

PubMedCentral® Posted Date

2-8-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Mice, Animals, Interleukin-10, Diet, High-Fat, Intestines, Macrophages, Lipids, Macrophages, Neutrophils, Immunology

Abstract

Chronic exposure to high-fat diets (HFD) worsens intestinal disease pathology, but acute effects of HFD in tissue damage remain unclear. Here, we used short-term HFD feeding in a model of intestinal injury and found sustained damage with increased cecal dead neutrophil accumulation, along with dietary lipid accumulation. Neutrophil depletion rescued enhanced pathology. Macrophages from HFD-treated mice showed reduced capacity to engulf dead neutrophils. Macrophage clearance of dead neutrophils activates critical barrier repair and antiinflammatory pathways, including IL-10, which was lost after acute HFD feeding and intestinal injury. IL-10 overexpression restored intestinal repair after HFD feeding and intestinal injury. Macrophage exposure to lipids from the HFD prevented tethering and uptake of apoptotic cells and Il10 induction. Milk fat globule-EGF factor 8 (MFGE8) is a bridging molecule that facilitates macrophage uptake of dead cells. MFGE8 also facilitates lipid uptake, and we demonstrate that dietary lipids interfere with MFGE8-mediated macrophage apoptotic neutrophil uptake and subsequent Il10 production. Our findings demonstrate that HFD promotes intestinal pathology by interfering with macrophage clearance of dead neutrophils, leading to unresolved tissue damage.

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