Maintenance of Macrophage Redox Status by ChREBP Limits Inflammation and Apoptosis and Protects against Advanced Atherosclerotic Lesion Formation

Creators: Sarrazy, Vincent; Sore, Sophie; Viaud, Manon; Rignol, Guylène; Westerterp, Marit; Ceppo, Franck; Tanti, Jean-Francois; Guinamard, Rodolphe; Gautier, Emmanuel; Yvan-Charvet, Laurent

Others:: Centre méditerranéen de médecine moléculaire (C3M) ; Université Nice Sophia Antipolis (1965 - 2019) (UNS) ; COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA); Columbia University [New York]; Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases [IHU ICAN] ; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN) ; CHU Pitié-Salpêtrière [AP-HP] ; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP] ; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Description

Enhanced glucose utilization can be visualized in atherosclerotic lesions and may reflect a high glycolytic rate in lesional macrophages, but its causative role in plaque progression remains unclear. We observe that the activity of the carbohydrate-responsive element binding protein ChREBP is rapidly downregulated upon TLR4 activation in macrophages. ChREBP inactivation refocuses cellular metabolism to a high redox state favoring enhanced inflammatory responses after TLR4 activation and increased cell death after TLR4 activation or oxidized LDL loading. Targeted deletion of ChREBP in bone marrow cells resulted in accelerated atherosclerosis progression in Ldlr(-/-) mice with increased monocytosis, lesional macrophage accumulation, and plaque necrosis. Thus, ChREBP-dependent macrophage metabolic reprogramming hinders plaque progression and establishes a causative role for leukocyte glucose metabolism in atherosclerosis.

Abstract

International audience

Maintenance of Macrophage Redox Status by ChREBP Limits Inflammation and Apoptosis and Protects against Advanced Atherosclerotic Lesion Formation

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