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Quantification of Monocyte Transmigration and Foam Cell Formation from Individuals with Chronic Inflammatory Conditions
Published on: October 17, 2017
Monocytes from HIV-infected individuals show impaired cholesterol efflux and increased foam cell formation after
Anna Maisa1, Anna C Hearps, Thomas A Angelovich
1aCentre for Biomedical Research, Burnet Institute bDepartment of Infectious Diseases, Monash University cSchool of Applied Sciences, RMIT University dMonash Micro Imaging, Monash University eDepartment of Microbiology and Immunology, Melbourne University, Melbourne, Victoria, Australia fFeinberg School of Medicine, Northwestern University, Chicago, Illinois, USA gDepartment of Immunology, Monash University, Melbourne, Victoria, Australia.
Insights
Monocytes from individuals with HIV show impaired cholesterol processing and are prone to forming foam cells, contributing to atherosclerosis. Elevated TNF levels in HIV+ serum exacerbate this process, even in treated individuals.
Area of Science:
- Immunology
- Cardiovascular Science
- Infectious Disease
Background:
- Individuals with Human Immunodeficiency Virus (HIV) have a higher risk of atherosclerosis and cardiovascular disease, independent of treatment and traditional risk factors.
- Monocytes are key players in atherosclerosis development, and HIV-related inflammation may drive this, but mechanisms remain unclear.
Purpose of the Study:
- To investigate the mechanisms by which HIV-infected monocytes contribute to atherosclerosis.
- To examine monocyte function, cholesterol metabolism, and foam cell formation in HIV+ individuals.
Main Methods:
- An in-vitro model of atherosclerotic plaque formation was used.
- Transendothelial migration, foam cell differentiation, cholesterol efflux, and gene expression of monocytes from HIV+ and uninfected donors were assessed.
Main Results:
- Monocytes from HIV+ individuals exhibited increased foam cell formation and impaired cholesterol efflux.
- Serum from virologically suppressed HIV+ individuals potentiated foam cell formation.
- Elevated plasma tumor necrosis factor (TNF) levels in HIV+ individuals correlated with increased foam cell formation, which was inhibited by TNF receptor blockade.
Conclusions:
- Monocytes from HIV+ individuals are primed for foam cell formation and display impaired cholesterol efflux.
- Elevated TNF levels in HIV+ serum enhance monocyte foam cell formation.
- The proatherogenic phenotype of monocytes persists in treated HIV+ individuals, potentially explaining increased atherosclerosis risk.
Design:
HIV-infected (HIV+) individuals have an increased risk of atherosclerosis and cardiovascular disease which is independent of antiretroviral therapy and traditional risk factors. Monocytes play a central role in the development of atherosclerosis, and HIV-related chronic inflammation and monocyte activation may contribute to increased atherosclerosis, but the mechanisms are unknown.
Methods:
Using an in-vitro model of atherosclerotic plaque formation, we measured the transendothelial migration of purified monocytes from age-matched HIV+ and uninfected donors and examined their differentiation into foam cells. Cholesterol efflux and the expression of cholesterol metabolism genes were also assessed.
Results:
Monocytes from HIV+ individuals showed increased foam cell formation compared with controls (18.9 vs. 0%, respectively, P = 0.004) and serum from virologically suppressed HIV+ individuals potentiated foam cell formation by monocytes from both uninfected and HIV+ donors. Plasma tumour necrosis factor (TNF) levels were increased in HIV+ vs. control donors (5.9 vs. 3.5 pg/ml, P = 0.02) and foam cell formation was inhibited by blocking antibodies to TNF receptors, suggesting a direct effect on monocyte differentiation to foam cells. Monocytes from virologically suppressed HIV+ donors showed impaired cholesterol efflux and decreased expression of key genes regulating cholesterol metabolism, including the cholesterol transporter ABCA1 (P = 0.02).
Conclusion:
Monocytes from HIV+ individuals show impaired cholesterol efflux and are primed for foam cell formation following transendothelial migration. Factors present in HIV+ serum, including elevated TNF levels, further enhance foam cell formation. The proatherogenic phenotype of monocytes persists in virologically suppressed HIV+ individuals and may contribute mechanistically to increased atherosclerosis in this population.
