Activation of NLRP3 inflammasome by cholesterol crystals in alcohol consumption induces atherosclerotic lesions
Open accessAbstract
Epidemiological studies showed a strong association between alcoholism and incidence of stroke, for which the underlying causative mechanisms remain to be understood. Here we found that infiltration of immune cells and deposition of cholesterol at the site of brain artery/capillary injury induced atherosclerosis in chronic alcohol (ethanol) consumption in the presence or absence of high-fat diet. Conversion of cholesterol into sharp edges of cholesterol crystals (CCs) in alcohol intake was key to activation of NLRP3 inflammasome, induction of cerebral atherosclerosis, and development of neuropathy around the atherosclerotic lesions. The presence of alcohol was critical for the formation of CCs and development of the neuropathology. Thus, we observed that alcohol consumption elevated the level of plasma cholesterol, deposition and crystallization of cholesterol, as well as activation of NLRP3 inflammasome. This led to arteriole or capillary walls thickening and increase intracranial blood pressure. Distinct neuropathy around the atherosclerotic lesions indicated vascular inflammation as an initial cause of neuronal degeneration. We demonstrated the molecular mechanisms of NLRP3 activation and downstream signaling cascade event in primary culture of human brain arterial/capillary endothelial cells in the setting of dose-/time-dependent effects of alcohol/CCs using NLRP3 gene silencing technique. We also detected CCs in blood samples from alcohol users, which validated the clinical importance of the findings. Finally, combined therapy of acetyl-l-carnitine and Lipitor® prevented deposition of cholesterol, formation of CCs, activation of NLRP3, thickening of vessel walls, and elevation of intracranial blood pressure. We conclude that alcohol-induced accumulation and crystallization of cholesterol activates NLRP3/caspase-1 in the cerebral vessel that leads to early development of atherosclerosis.
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Primed macrophages secrete large amounts of IL-1β in response to cholesterol crystals in an NLRP3 inflammasome-dependent manner in mouse and human cells.
“Primed macrophages secrete large amounts of IL‐1β in response to cholesterol crystals in an NLRP3 inflammasome‐dependent manner in mouse and human cells.34, 35”
From Trimethylamine‐N‐Oxide Induces Vascular Inflammation by Activating the NLRP3 Inflammasome Through the SIRT3‐SOD2‐mtROS Signaling Pathway (2017) · cites this paper as [35]
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- Authors
- Abdul Muneer, P. M., Alikunju, S., Mishra, V., Schuetz, H., Szlachetka, A. M., Burnham, E. L., & Haorah, J.
- Affiliations
- University of Nebraska Medical Center (US)
- New Jersey Institute of Technology (US)
- University of Colorado Anschutz (US)
- Corresponding author
- Haorah, James
- Venue
- Brain, Behavior, and Immunity
- Publisher
- Elsevier BV
- Published
- 2017-05
- Volume
- 62
- Pages
- 291-305
- ISSN
- 0889-1591 (ISSN-L)
- PMC
- PMC6378699
- OpenAlex
- W2590082358
- Cited by
- 33
- References
- 39
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 1 · 2023: 2 · 2022: 5 · 2021: 3 · 2020: 1 · 2019: 7 · 2018: 4 · 2017: 3
- FWCI
- 1.68
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Brain Behavior and Immunity (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- University of Nebraska Medical Center
- National Institutes of Health (5r21aa022734-02)
- National Institute on Alcohol Abuse and Alcoholism (R21AA020370, R21 AA022734, R24AA019661)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
- Keywords
- NLRP3 inflammasome, cholesterol crystals, chronic alcohol consumption, cerebral atherosclerosis, caspase-1, vascular inflammation, endothelial cells, neuropathy, acetyl-L-carnitine, atorvastatin, stroke, high-fat diet, cholesterol deposition
- MeSH terms
- NLR Family, Pyrin Domain-Containing 3 Protein, Alcohol Drinking, Animals, Blood Pressure, Brain, Cholesterol, Humans, Male, Rats, Sprague-Dawley, Atherosclerosis, Rats, Inflammasomes, Diet, High-Fat
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