title: Activation of NLRP3 inflammasome by cholesterol crystals in alcohol consumption induces atherosclerotic lesions.
abstract: 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.
authors.affiliation: Laboratory of Neurovascular Inflammation and Neurodegeneration, Department of Biomedical Engineering, Center for Injury Bio Mechanics, Materials and Medicine, New Jersey Institute of Technology, Newark, NJ 07102, United States; Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, United States.
authors.forename: P M Abdul
authors.initials: PMA
authors.lastname: Muneer
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, United States.
authors.forename: Saleena
authors.initials: S
authors.lastname: Alikunju
authors.affiliation: Laboratory of Neurovascular Inflammation and Neurodegeneration, Department of Biomedical Engineering, Center for Injury Bio Mechanics, Materials and Medicine, New Jersey Institute of Technology, Newark, NJ 07102, United States; Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, United States.
authors.forename: Vikas
authors.initials: V
authors.lastname: Mishra
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, United States.
authors.forename: Heather
authors.initials: H
authors.lastname: Schuetz
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, United States.
authors.forename: Adam M
authors.initials: AM
authors.lastname: Szlachetka
authors.affiliation: Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado School of Medicine, Aurora, CO 80045, United States.
authors.forename: Ellen L
authors.initials: EL
authors.lastname: Burnham
authors.affiliation: Laboratory of Neurovascular Inflammation and Neurodegeneration, Department of Biomedical Engineering, Center for Injury Bio Mechanics, Materials and Medicine, New Jersey Institute of Technology, Newark, NJ 07102, United States; Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, United States. Electronic address: james.haorah@njit.edu.
authors.forename: James
authors.initials: J
authors.lastname: Haorah
mesh_terms: D000428:Alcohol Drinking / Q000378:metabolism*; D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism*; D001794:Blood Pressure / Q000502:physiology; D001921:Brain / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism*; D059305:Diet, High-Fat; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D008297:Male; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D002784:Cholesterol
keywords: Alcohol-induced cholesterol crystals; Cerebral atherosclerosis; Intracranial blood pressure; NLRP3 inflammasomes; Therapeutic intervention