MicroRNA-33 regulates the innate immune response via ATP binding cassette transporter-mediated remodeling of membrane microdomains
Open accessAbstract
MicroRNAs (miRNAs) are short non-coding RNAs that regulate gene expression by promoting degradation and/or repressing translation of specific target mRNAs. Several miRNAs have been identified that regulate the amplitude of the innate immune response by directly targeting Toll-like receptor (TLR) pathway members and/or cytokines. miR-33a and miR-33b (the latter present in primates but absent in rodents and lower species) are located in introns of the sterol regulatory element-binding protein (SREBP)-encoding genes and control cholesterol/lipid homeostasis in concert with their host gene products. These miRNAs regulate macrophage cholesterol by targeting the lipid efflux transporters ATP binding cassette (ABC)A1 and ABCG1. We and others have previously reported that Abca1(-/-) and Abcg1(-/-) macrophages have increased TLR proinflammatory responses due to augmented lipid raft cholesterol. Given this, we hypothesized that miR-33 would augment TLR signaling in macrophages via a raft cholesterol-dependent mechanism. Herein, we report that multiple TLR ligands down-regulate miR-33 in murine macrophages. In the case of lipopolysaccharide, this is a delayed, Toll/interleukin-1 receptor (TIR) domain-containing adapter-inducing interferon-β-dependent response that also down-regulates Srebf-2, the host gene for miR-33. miR-33 augments macrophage lipid rafts and enhances proinflammatory cytokine induction and NF-κB activation by LPS. This occurs through an ABCA1- and ABCG1-dependent mechanism and is reversible by interventions upon raft cholesterol and by ABC transporter-inducing liver X receptor agonists. Taken together, these findings extend the purview of miR-33, identifying it as an indirect regulator of innate immunity that mediates bidirectional cross-talk between lipid homeostasis and inflammation.
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Lai L and colleagues reported that absence of miR-33 in macrophages alters membrane microdomains, influencing innate immune response.
“Lai L and colleagues have recently reported that absence of miR-33 in Mθs alters membrane microdomains, influencing the innate immune response (Lai et al., 2016).”
From Genetic dissection of the impact of miR-33a and miR-33b during the progression of atherosclerosis (2017) · cites this paper as Lai et al., 2016
Cites
MicroRNA-33 and the SREBP Host Genes Cooperate to Control Cholesterol Homeostasis
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“Lastly, given that cellular cholesterol overload can also induce inflammation through endoplasmic reticulum stress (40) and inflammasome activation (41), the potential also exists for miR-33 to impact these inflammatory mechanisms.”
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Control of Cholesterol Metabolism and Plasma High-Density Lipoprotein Levels by microRNA-144
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“These include miR-758 (42), miR-26 (43), miR-106b (44), miR-10b (45), miR-144 (46, 47), and miR-101 (48).”
miR-106b impairs cholesterol efflux and increases Aβ levels by repressing ABCA1 expression
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“These include miR-758 (42), miR-26 (43), miR-106b (44), miR-10b (45), miR-144 (46, 47), and miR-101 (48).”
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Genetic dissection of the impact of miR-33a and miR-33b during the progression of atherosclerosis
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The lipid paradox in neuroprogressive disorders: Causes and consequences
Morris, G., Berk, M., Walder, K., O’Neil, A., Maes, M., & Puri, B. K. (2021) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2021.06.017 · Cited by 17 · see citing works
- Authors
- Lai, L., Azzam, K. M., Lin, W.-C., Rai, P., Lowe, J. M., Gabor, K. A., Madenspacher, J. H., Aloor, J. J., Parks, J. S., Näär, A. M., & Fessler, M. B.
- Affiliations
- National Institutes of Health (US)
- Wake Forest University Health Sciences (US)
- Harvard University (US)
- Corresponding author
- Fessler, Michael B.
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2016-09
- Volume
- 291
- Issue
- 37
- Pages
- 19651-19660
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC5016698
- OpenAlex
- W2498460930
- Cited by
- 67
- References
- 9
- Citations by year
- 2026: 2 · 2025: 9 · 2024: 4 · 2023: 9 · 2022: 3 · 2021: 6 · 2020: 6 · 2019: 12 · 2018: 6 · 2017: 8 · 2016: 2
- FWCI
- 5.66
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Environmental Health Sciences (Z01 ES102005)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Keywords
- miR-33, miR-33a, miR-33b, innate immunity, Toll-like receptor signaling, macrophages, lipid rafts, cholesterol, ABCA1, ABCG1, SREBP2, NF-κB activation, inflammatory cytokines, lipopolysaccharide, TIRAP, liver X receptor agonist, lipid homeostasis, inflammation
- MeSH terms
- RAW 264.7 Cells, ATP Binding Cassette Transporter, Subfamily G, Member 1, Animals, Immunity, Innate, Macrophages, Mice, Knockout, Membrane Microdomains, MicroRNAs, Mice, Sterol Regulatory Element Binding Protein 2, ATP Binding Cassette Transporter 1
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