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Oxysterol Restraint of Cholesterol Synthesis Prevents AIM2 Inflammasome Activation
Open accessAbstract
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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“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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“Dang et al. later showed that up-regulating CH25H and 25-HC production reduce inflammasome activity and IL-1β levels in LPS-activated macrophages [100].”
From 25-Hydroxycholesterol amplifies microglial IL-1β production in an apoE isoform-dependent manner (2020) · cites this paper as [100]
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“25-HC has also been reported to have both anti- (Reboldi et al., 2014; Dang et al., 2017) and proinflammatory (Gold et al., 2014; Fu et al., 2014) actions depending on the model system and context.”
From Cholesterol 25-hydroxylase mediates neuroinflammation and neurodegeneration in a mouse model of tauopathy (2024) · cites this paper as Dang et al., 2017
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Metadata
- 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.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2017-11
- Volume
- 171
- Issue
- 5
- Pages
- 1057-1071.e11
- ISSN
- 0092-8674 (ISSN-L)
- 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
- 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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