Loss of ABCG1 influences regulatory T cell differentiation and atherosclerosis

Cheng, Hao-Yuan; Gaddis, Dalia E.; Wu, Runpei; McSkimming, Chantel; Haynes, LaTeira D.; Taylor, Angela M.; McNamara, Coleen A.; Sorci‐Thomas, Mary G.; Hedrick, Catherine C.

doi:10.1172/jci83136

Cited by 67 publications

(74 citation statements)

References 51 publications

(56 reference statements)

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“…2, 3). These data demonstrate that ABCG1 expression in T2 cells not only regulates T2 surfactant lipid homeostasis, but also immune response and immunoglobulins, consistent with previous reports that ABCG1 plays important roles in both lipid homeostasis and immunity (30,38,52,(68)(69)(70)(71)(72)(73)(74). Loss of ABCG1 in T2 cells compromises their ability to secrete and/or recycle surfactant lipids, resulting in hypertrophied cells that accumulate enlarged lamellar bodies [(28) and this study].…”

Section: Discussionsupporting

confidence: 92%

ABCG1 regulates pulmonary surfactant metabolism in mice and men

Vallim

Lee

Merriott

et al. 2017

Journal of Lipid Research

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Idiopathic pulmonary alveolar proteinosis (PAP) is a rare lung disease characterized by accumulation of surfactant. Surfactant synthesis and secretion are restricted to epithelial type 2 (T2) pneumocytes (also called T2 cells). Clearance of surfactant is dependent upon T2 cells and macrophages. ABCG1 is highly expressed in both T2 cells and macrophages. ABCG1-deficient mice accumulate surfactant, lamellar body-loaded T2 cells, lipid-loaded macrophages, B-1 lymphocytes, and immunoglobulins, clearly demonstrating that ABCG1 has a critical role in pulmonary homeostasis. We identify a variant in the promoter in patients with PAP that results in impaired activation of by the liver X receptor α, suggesting that ABCG1 basal expression and/or induction in response to sterol/lipid loading is essential for normal lung function. We generated mice lacking ABCG1 specifically in either T2 cells or macrophages to determine the relative contribution of these cell types on surfactant lipid homeostasis. These results establish a critical role for T2 cell ABCG1 in controlling surfactant and overall lipid homeostasis in the lung and in the pathogenesis of human lung disease.

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Section: Discussionsupporting

confidence: 92%

ABCG1 regulates pulmonary surfactant metabolism in mice and men

Vallim

Lee

Merriott

et al. 2017

Journal of Lipid Research

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“…For example, T cells from mice deficient in the cholesterol transporter ABCG1 show increased proliferative responses to TCR stimulation, and T cell-selective deletion of the Abcg1 gene results in an increase in Treg cell differentiation from naïve T cells (Armstrong et al, 2010). T cell- or Treg-cell-restricted ABCG1 deficiency in Ldlr //- mice results in more Treg, less Teff cells, and less atherosclerosis compared to control mice (Cheng et al, 2016). Interestingly, the ABCG1-deficient T cells accumulate more cholesterol in lysosomes than control T cells, which lead to inhibition of mTOR-mediated STAT5 signaling.…”

Section: An Increase In the Ratio Of Effector T Cells To Regulatory Tmentioning

confidence: 99%

“…In two of the previously discussed studies, exposure of T cells to excess cholesterol, either through systemic hypercholesterolemia (Mailer et al, 2017) or by impairing cholesterol efflux by deleting ABCG1 (Cheng et al, 2016), was shown to favor Treg over Teff cell differentiation. This may seem surprising, given the atheroprotective effect of Treg cells and the pro-atherogenic and pro-inflammatory effects of excess cholesterol and Teff cells.…”

Section: An Increase In the Ratio Of Effector T Cells To Regulatory Tmentioning

confidence: 99%

Monocyte-Macrophages and T Cells in Atherosclerosis

2017

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Atherosclerosis is an arterial disease process characterized by the focal subendothelial accumulation of apolipoprotein B-lipoproteins, immune and vascular wall cells, and extracellular matrix. The lipoproteins acquire features of damage-associated molecular patterns and trigger first an innate immune response, dominated by monocyte-macrophages, and then an adaptive immune response. These inflammatory responses often become chronic and non-resolving, leading to arterial damage and thrombosis-induced organ infarction. The innate immune response is regulated at various stages, from hematopoiesis through monocyte changes and macrophage activation. The adaptive immune response is regulated primarily by mechanisms that affect the balance of regulatory vs. effector T cells. Mechanisms related to cellular cholesterol, phenotypic plasticity, metabolism, and aging play key roles in regulating these responses. Herein we review select topics that shed light on these processes and suggest new treatment strategies.

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“…Treg functions seem particularly sensitive to cholesterol levels. Inhibition of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR), which controls cholesterol synthesis, prevented Treg proliferation and impaired Treg function (62), and Abcg1 deletion increased Treg proliferation (63). In the LDLR knockout model of hyperlipidemia, increases in the splenic frequency of Tregs were correlated with changes in phenotype and their functional inability to control atherosclerotic lesions (64).…”

Section: Impact Of Pollutants On Graft Outcomementioning

confidence: 99%