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Proc Natl Acad Sci U S A. 2018 Dec 26;115(52):E12228-E12234. doi: 10.1073/pnas.1813458115. Epub 2018 Dec 10.

SREBP-1a-stimulated lipid synthesis is required for macrophage phagocytosis downstream of TLR4-directed mTORC1.

Lee JH1, Phelan P2,3, Shin M4, Oh BC5,6, Han X2,3,7,8,9, Im SS10, Osborne TF11,3.

Author information

1
Department of Physiology, Keimyung University School of Medicine, 42601 Daegu, South Korea.
2
Institute for Fundamental Biomedical Research, Johns Hopkins University School of Medicine, St. Petersburg, FL 33701.
3
Department of Medicine, Johns Hopkins University School of Medicine, St. Petersburg, FL 33701.
4
Department of Microbiology, School of Medicine, Kyungpook National University, 41944 Daegu, South Korea.
5
Lee Gil Ya Cancer and Diabetes Institute, College of Medicine, Gachon University, 21999 Incheon, Korea.
6
Department of Physiology, College of Medicine, Gachon University, 21999 Incheon, South Korea.
7
Barshop Institute for Longevity and Aging Studies, University of Texas Health Sciences Center, San Antonio, TX 78229.
8
Department of Medicine, University of Texas Health Sciences Center, San Antonio, TX 78229.
9
Department of Biochemistry, University of Texas Health Sciences Center, San Antonio, TX 78229.
10
Department of Physiology, Keimyung University School of Medicine, 42601 Daegu, South Korea; ssim73@kmu.ac.kr tosborn9@jhmi.edu.
11
Institute for Fundamental Biomedical Research, Johns Hopkins University School of Medicine, St. Petersburg, FL 33701; ssim73@kmu.ac.kr tosborn9@jhmi.edu.

Abstract

There is a growing appreciation for a fundamental connection between lipid metabolism and the immune response. Macrophage phagocytosis is a signature innate immune response to pathogen exposure, and cytoplasmic membrane expansion is required to engulf the phagocytic target. The sterol regulatory element binding proteins (SREBPs) are key transcriptional regulatory proteins that sense the intracellular lipid environment and modulate expression of key genes of fatty acid and cholesterol metabolism to maintain lipid homeostasis. In this study, we show that TLR4-dependent stimulation of macrophage phagocytosis requires mTORC1-directed SREBP-1a-dependent lipid synthesis. We also show that the phagocytic defect in macrophages from SREBP-1a-deficient mice results from decreased interaction between membrane lipid rafts and the actin cytoskeleton, presumably due to reduced accumulation of newly synthesized fatty acyl chains within major membrane phospholipids. We show that mTORC1-deficient macrophages also have a phagocytic block downstream from TLR4 signaling, and, interestingly, the reduced level of phagocytosis in both SREBP-1a- and mTORC1-deficient macrophages can be restored by ectopic SREBP-1a expression. Taken together, these observations indicate SREBP-1a is a major downstream effector of TLR4-mTORC1 directed interactions between membrane lipid rafts and the actin cytoskeleton that are required for pathogen-stimulated phagocytosis in macrophages.

KEYWORDS:

SREBPs; TLR4; lipid synthesis; mTORC1; macrophages

PMID:
30530672
PMCID:
PMC6310840
DOI:
10.1073/pnas.1813458115
[Indexed for MEDLINE]
Free PMC Article

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