quantification-monocyte-transmigration-foam-cell-formation-from

Quantification of Monocyte Transmigration and Foam Cell Formation from Individuals with Chronic Inflammatory Conditions

Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Atherosclerosis, a leading cause of CAD, is initiated by the ...

cell-free-biochemical-fluorometric-enzymatic-assay-for-high

Cell-free Biochemical Fluorometric Enzymatic Assay for High-throughput Measurement of Lipid Peroxidation in High Density Lipoprotein

Low high-density lipoprotein cholesterol (HDL-C) levels are one of the most powerful independent negative predictors of atherosclerotic cardiovascular ...

Burnet Institute

RMIT University

The increased life expectancy of HIV-infected individuals due to improved treatment has revealed an unexpected increase in non-AIDS comorbidities that are typically associated with older age including cardiovascular disease, dementia and frailty. The majority of these diseases arise as the result of dysregulated systemic inflammation, and both the aged and HIV-infected individuals exhibit elevated basal levels of inflammation. In the elderly, increased inflammation and age-related diseases are associated with a state of impaired immunity called immunosenescence, which is thought to result from a lifetime of immune stimulation. It is now apparent that HIV induces premature immunosenescence within T-cells; however, the impact of HIV on aging of cells of the innate arm of the immune system is unknown. Innate immune cells play a central role in inflammation and are thus critical for the pathogenesis of inflammatory diseases. Limited evidence suggests HIV infection mimics age-related changes to innate immune cells; however, the extent of this effect and the mechanism underlying these changes remain to be defined. This review focuses on the impact of HIV infection on the function and aging of innate immune cells and discusses potential drivers of premature immunosenescence including chronic endotoxaemia, residual viraemia, telomere attrition and altered cellular signalling.

HIV infection and aging of the innate immune system.

To compare the impact of HIV infection and healthy ageing on monocyte phenotype and function and determine whether age-related changes induced by HIV are reversed in antiretroviral treated individuals.

HIV infection induces age-related changes to monocytes and innate immune activation in young men that persist despite combination antiretroviral therapy.

Chronic inflammation in older individuals is thought to contribute to inflammatory, age-related diseases. Human monocytes are comprised of three subsets (classical, intermediate and nonclassical subsets), and despite being critical regulators of inflammation, the effect of age on the functionality of monocyte subsets remains to be fully defined. In a cross-sectional study involving 91 healthy male (aged 20-84 years, median 52.4) and 55 female (aged 20-82 years, median 48.3) individuals, we found age was associated with an increased proportion of intermediate and nonclassical monocytes (P = 0.002 and 0.04, respectively) and altered phenotype of specific monocyte subsets (e.g. increased expression of CD11b and decreased expression of CD38, CD62L and CD115). Plasma levels of the innate immune activation markers CXCL10, neopterin (P < 0.001 for both) and sCD163 (P = 0.003) were significantly increased with age. Whilst similar age-related changes were observed in both sexes, monocytes from women were phenotypically different to men [e.g. lower proportion of nonclassical monocytes (P = 0.002) and higher CD115 and CD62L but lower CD38 expression] and women exhibited higher levels of CXCL10 (P = 0.012) and sCD163 (P < 0.001) but lower sCD14 levels (P < 0.001). Monocytes from older individuals exhibit impaired phagocytosis (P < 0.05) but contain shortened telomeres (P < 0.001) and significantly higher intracellular levels of TNF both at baseline and following TLR4 stimulation (P < 0.05 for both), suggesting a dysregulation of monocyte function in the aged. These data show that aging is associated with chronic innate immune activation and significant changes in monocyte function, which may have implications for the development of age-related diseases.

Aging is associated with chronic innate immune activation and dysregulation of monocyte phenotype and function.

Aging is associated with immune dysfunction and the related development of conditions with an inflammatory pathogenesis. Some of these immune changes are also observed in HIV infection, but the interaction between immune changes with aging and HIV infection are unknown. Whilst sex differences in innate immunity are recognized, little research into innate immune aging has been performed on women.

Age-associated changes in monocyte and innate immune activation markers occur more rapidly in HIV infected women.

Combined antiretroviral therapy (cART) extends the lifespan and the quality of life for HIV-infected persons but does not completely eliminate chronic immune activation and inflammation. The low level of chronic immune activation persisting during cART-treated HIV infection is associated with the development of diseases which usually occur in the elderly. Although T-cell activation has been extensively examined in the context of cART-treated HIV infection, monocyte activation is only beginning to be recognized as an important source of inflammation in this context. Here we examine markers and sources of monocyte activation during cART-treated HIV infection and discuss the role of monocytes during cardiovascular disease, HIV-associated neurocognitive disorder, and innate immune aging.

Monocytes as regulators of inflammation and HIV-related comorbidities during cART.

Chronic inflammation and immune activation occur in both HIV infection and normal aging and are associated with inflammatory disease. However, the degree to which HIV influences age-related innate immune changes, and the biomarkers which best reflect them, remains unclear.

Viremic and Virologically Suppressed HIV Infection Increases Age-Related Changes to Monocyte Activation Equivalent to 12 and 4 Years of Aging, Respectively.

Atherosclerosis is the leading cause of cardiovascular disease and is both a metabolic and inflammatory disease. Two models describe early events initiating atherosclerotic plaque formation, whereby foam cells form in response to hyperlipidaemia or inflammation-associated stimuli. Although these models are inextricably linked and not mutually exclusive, identifying the unique contribution of each in different disease settings remains an important question. Circulating monocytes are key mediators of atherogenesis in both models as precursors to lipid-laden foam cells formed in response to either excess lipid deposition in arteries, signalling via pattern-associated molecular patterns or a combination of the two. In this review, we assess the role of monocytes in each model and discuss how key steps in atherogenesis may be targeted to enhance clinical outcomes in patients with chronic inflammatory disease.

Inflammation-induced foam cell formation in chronic inflammatory disease.

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.

Monocytes from HIV-infected individuals show impaired cholesterol efflux and increased foam cell formation after transendothelial migration.

Aging is the strongest predictor of cardiovascular diseases such as atherosclerosis, which are the leading causes of morbidity and mortality in elderly men. Monocytes play an important role in atherosclerosis by differentiating into foam cells (lipid-laden macrophages) and producing atherogenic proinflammatory cytokines. Monocytes from the elderly have an inflammatory phenotype that may promote atherosclerotic plaque development; here we examined whether they are more atherogenic than those from younger individuals. Using an in vitro model of monocyte transmigration and foam cell formation, monocytes from older men (median age [range]: 75 [58-85] years, n=20) formed foam cells more readily than those of younger men (32 [23-46] years, n=20) (P<0.003) following transmigration across a TNF-activated endothelial monolayer. Compared to young men, monocytes from the elderly had impaired cholesterol efflux and lower expression of regulators of cholesterol transport and metabolism. Foam cell formation was enhanced by soluble factors in serum from older men, but did not correlate with plasma lipid levels. Of the three subsets, intermediate monocytes formed the most foam cells. Therefore, both cellular changes to monocytes and soluble plasma factors in older men primes monocytes for foam cell formation following transendothelial migration, which may contribute to enhanced atherosclerosis in this population.

Ex vivo foam cell formation is enhanced in monocytes from older individuals by both extrinsic and intrinsic mechanisms.

Eradication of HIV cannot be achieved with combination antiretroviral therapy (cART) because of the persistence of long-lived latently infected resting memory CD4(+) T cells. We previously reported that HIV latency could be established in resting CD4(+) T cells in the presence of the chemokine CCL19. To define how CCL19 facilitated the establishment of latent HIV infection, the role of chemokine receptor signalling was explored.

HIV integration and the establishment of latency in CCL19-treated resting CD4(+) T cells require activation of NF-κB.

Innate immune dysfunction persists in HIV(+) individuals despite effective combination antiretroviral therapy (cART). We recently demonstrated that an adaptive-like CD56(dim) NK cell population lacking the signal transducing protein FcRγ is expanded in HIV(+) individuals. Here, we analyzed a cohort of HIV(+) men who have sex with men (MSM, n = 20) at baseline and following 6, 12, and 24 months of cART and compared them with uninfected MSM (n = 15) to investigate the impact of cART on NK cell dysfunction. Proportions of NK cells expressing markers of early (CD69(+)) and late (HLA-DR(+)/CD38(+)) activation were elevated in cART-naïve HIV(+) MSM (p = 0.004 and 0.015, respectively), as were FcRγ(-) NK cells (p = 0.003). Using latent growth curve modeling, we show that cART did not reduce levels of FcRγ(-) NK cells (p = 0.115) or activated HLA-DR(+)/CD38(+) NK cells (p = 0.129) but did reduce T cell and monocyte activation (p < 0.001 for all). Proportions of FcRγ(-) NK cells were not associated with NK cell, T cell, or monocyte activation, suggesting different factors drive CD56(dim) FcRγ(-) NK cell expansion and immune activation in HIV(+) individuals. While proportions of activated CD69(+) NK cells declined significantly on cART (p = 0.003), the rate was significantly slower than the decline of T cell and monocyte activation, indicating a reduced potency of cART against NK cell activation. Our findings indicate that 2 years of suppressive cART have no impact on CD56(dim) FcRγ(-) NK cell expansion and that NK cell activation persists after normalization of other immune parameters. This may have implications for the development of malignancies and co-morbidities in HIV(+) individuals on cART.

Persistence of Activated and Adaptive-Like NK Cells in HIV(+) Individuals despite 2 Years of Suppressive Combination Antiretroviral Therapy.

The role of HDL function in HIV-related atherosclerotic cardiovascular disease (CVD) is unclear. HDLs isolated from HIV+ [HIV(+)HDL] and HIV-uninfected individuals (HDL) were assessed for HDL function and ability to promote monocyte-derived foam cell formation (MDFCF) (a key event in HIV-related CVD) ex vivo.

ArticleTotal : 2	Year
Publication title Cited by 17	2017
Publication title Cited by 15	2017

Article	Year
HIV infection and aging of the innate immune system. Sexual health\| PubMed ID: 22127030	2011
HIV infection induces age-related changes to monocytes and innate immune activation in young men that persist despite combination antiretroviral therapy. AIDS (London, England)\| PubMed ID: 22313961	2012
Aging is associated with chronic innate immune activation and dysregulation of monocyte phenotype and function. Aging cell\| PubMed ID: 22708967	2012
Age-associated changes in monocyte and innate immune activation markers occur more rapidly in HIV infected women. PloS one\| PubMed ID: 23365694	2013
Monocytes as regulators of inflammation and HIV-related comorbidities during cART. Journal of immunology research\| PubMed ID: 25025081	2014
Viremic and Virologically Suppressed HIV Infection Increases Age-Related Changes to Monocyte Activation Equivalent to 12 and 4 Years of Aging, Respectively. Journal of acquired immune deficiency syndromes (1999)\| PubMed ID: 25647525	2015
Inflammation-induced foam cell formation in chronic inflammatory disease. Immunology and cell biology\| PubMed ID: 25753272	2015
Monocytes from HIV-infected individuals show impaired cholesterol efflux and increased foam cell formation after transendothelial migration. AIDS (London, England)\| PubMed ID: 26244384	2015
Ex vivo foam cell formation is enhanced in monocytes from older individuals by both extrinsic and intrinsic mechanisms. Experimental gerontology\| PubMed ID: 27073169	2016
HIV integration and the establishment of latency in CCL19-treated resting CD4(+) T cells require activation of NF-κB. Retrovirology\| PubMed ID: 27459960	2016
Persistence of Activated and Adaptive-Like NK Cells in HIV(+) Individuals despite 2 Years of Suppressive Combination Antiretroviral Therapy. Frontiers in immunology\| PubMed ID: 28713370	2017
Dysfunctional HDL from HIV+ individuals promotes monocyte-derived foam cell formation in vitro. AIDS (London, England)\| PubMed ID: 28926407	2017

Thomas A. Angelovich

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