Oxysterol Restraint of Cholesterol Synthesis Prevents AIM2 Inflammasome Activation

Dang, Eric V.; McDonald, Jeffrey G.; Russell, David W.; Cyster, Jason G.

doi:10.1016/j.cell.2017.09.029

Cited by 355Inflammasome and immune disordersImmune Response and Inflammationinterferon and immune responses

Oxysterol Restraint of Cholesterol Synthesis Prevents AIM2 Inflammasome Activation

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Dang, Eric V., McDonald, Jeffrey G., Russell, David W., Cyster, Jason G.·2017·Cell

DOI 10.1016/j.cell.2017.09.029PMC PMC5693620

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Abstract

Type I interferon restrains interleukin-1β (IL-1β)-driven inflammation in macrophages by upregulating cholesterol-25-hydroxylase (Ch25h) and repressing SREBP transcription factors. However, the molecular links between lipid metabolism and IL-1β production remain obscure. Here, we demonstrate that production of 25-hydroxycholesterol (25-HC) by macrophages is required to prevent inflammasome activation by the DNA sensor protein absent in melanoma 2 (AIM2). We find that in response to bacterial infection or lipopolysaccharide (LPS) stimulation, macrophages upregulate Ch25h to maintain repression of SREBP2 activation and cholesterol synthesis. Increasing macrophage cholesterol content is sufficient to trigger IL-1β release in a crystal-independent but AIM2-dependent manner. Ch25h deficiency results in cholesterol-dependent reduced mitochondrial respiratory capacity and release of mitochondrial DNA into the cytosol. AIM2 deficiency rescues the increased inflammasome activity observed in Ch25h-/-. Therefore, activated macrophages utilize 25-HC in an anti-inflammatory circuit that maintains mitochondrial integrity and prevents spurious AIM2 inflammasome activation.

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Loss of Ch25h and 25HC promotes IL-1β production in mouse macrophages, whereas 25HC amplifies IL-1β secretion in an ApoE-dependent manner in mouse microglia.
“While loss of Ch25h and 25HC promoted interleukin 1-beta production in mouse macrophages (14,15), 25HC amplified interleukin 1-beta secretion in an ApoEdependent manner in mouse microglia (8).”
From Regulation of astrocyte lipid metabolism and ApoE secretion by the microglial oxysterol, 25-hydroxycholesterol (2023) · cites this paper as [15]

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The Importance of "Negative" Results - Lipid Lessons in Coronavirus Biology
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Authors: Dang, E. V., McDonald, J. G., Russell, D. W., & Cyster, J. G.
Affiliations: Howard Hughes Medical Institute (US)
The University of Texas Southwestern Medical Center (US)
Corresponding author: Dang, Eric V.
Cyster, Jason G.
ORCID: Dang, Eric V.
McDonald, Jeffrey G.
Russell, David W.
Cyster, Jason G.
Venue: Cell
Publisher: Elsevier BV
Published: 2017-11
Volume: 171
Issue: 5
Pages: 1057-1071.e11
ISSN: 0092-8674 (ISSN-L)
DOI: 10.1016/j.cell.2017.09.029
PMC: PMC5693620
OpenAlex: W2763382180
Cited by: 348
References: 43
Citations by year: 2026: 34 · 2025: 47 · 2024: 55 · 2023: 49 · 2022: 46 · 2021: 31 · 2020: 35 · 2019: 25 · 2018: 25
FWCI: 9.25
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 380 d)
Locations: Cell (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
eScholarship (California Digital Library) (submittedVersion)
Funders: UCSF DRC Center (P30 DK063720)
NIH (F30AI120527, AI040098, HL20948)
UCSF Medical Scientist Training Program (MSTP)
NIGMS (T32GM007618)
Howard Hughes Medical Institute
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
Keywords: oxysterols, 25-hydroxycholesterol, cholesterol biosynthesis, AIM2 inflammasome, IL-1β, macrophages, cholesterol 25-hydroxylase, SREBP2, lipid metabolism, mitochondrial DNA release, mitochondrial respiration, lipopolysaccharide, bacterial infection, type I interferon
MeSH terms: Oxysterols, Animals, Cholesterol, DNA-Binding Proteins, DNA, Mitochondrial, Humans, Hydroxycholesterols, Inflammation, Listeriosis, Listeria monocytogenes, Macrophages, Membrane Proteins, Mitochondria, Intracellular Signaling Peptides and Proteins, Mice, Interleukin-1beta, Inflammasomes

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Oxysterol Restraint of Cholesterol Synthesis Prevents AIM2 Inflammasome Activation

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