Mitochondrial Metabolic Reprogramming by CD36 Signaling Drives Macrophage Inflammatory Responses

Abstract

Rationale: A hallmark of chronic inflammatory disorders is persistence of pro-inflammatory macrophages in diseased tissues. In atherosclerosis this is associated with dyslipidemia and oxidative stress, but mechanisms linking these phenomena to macrophage activation remain incompletely understood. Objective: To investigate mechanisms linking dyslipidemia, oxidative stress and macrophage activation through modulation of immunometabolism, and to explore therapeutic potential targeting specific metabolic pathways. Methods and Results: Using a combination of biochemical, immunological, and ex vivo cell metabolic studies, we report that CD36 mediates a mitochondrial metabolic switch from oxidative phosphorylation to superoxide production in response to its ligand, oxLDL. Mitochondrial-specific inhibition of superoxide inhibited oxLDL-induced NF-κB activation and inflammatory cytokine generation. RNAseq, flow cytometry, 3H-labeled palmitic acid uptake, lipidomic analysis, confocal and EM imaging, and functional energetics revealed that oxLDL upregulated effectors of long-chain fatty acid (FA) uptake and mitochondrial import, while downregulating FA oxidation and inhibiting ATP5A, an electron transport chain (ETC) component. The combined effect is long-chain FA accumulation, alteration of mitochondrial structure and function, repurposing of the ETC to superoxide production, and NF-κB activation. Apoe null mice challenged with high fat diet showed similar metabolic changes in circulating Ly6C+ monocytes and peritoneal macrophages, along with increased CD36 expression. Moreover, mitochondrial ROS was positively correlated with CD36 expression in aortic lesional macrophages. Conclusions: These findings reveal that oxLDL/CD36 signaling in macrophages links dys-regulated FA metabolism to oxidative stress from the mitochondria, which drives chronic inflammation. Thus, targeting to CD36 and its downstream effectors may serve as potential new strategies against chronic inflammatory diseases such as atherosclerosis.

Origins and diversity of macrophages in health and disease

“…184 Oxidised LDL also can bind to CD36 on macrophages and suppress oxidative phosphorylation leading to mitochondrial ROS production, which drives chronic inflammation. 185 Macrophages exposed to extracellular pathogenic lipids can activate a triggering receptor expressed on myeloid cells 2 (TREM2)-dependent gene response involved in phagocytosis and lipid catabolism. 186,187 TREM2 expression is required for a metabolic switch towards glycolysis and is essential for the maintenance of healthy energy metabolism under conditions of stress.…”

The Emerging Role of MicroRNAs in NAFLD: Highlight of MicroRNA-29a in Modulating Oxidative Stress, Inflammation, and Beyond

“…In 2019, Chen et al reported that ox-LDL/CD36 signaling in macrophage links dysregulated FA metabolism and oxidative stress from the mitochondria, which drove chronic inflammation in the atherosclerosis model [122]. Our group also discovered that miR-29a protects against glucocorticoid-mediated osteoporosis by suppressing the activity of osteoclasts and differentiating from macrophages [128], thus supporting its role in regulating immune cell activity.…”

“…FAO primarily occurs in mitochondria, as well as in peroxisomes and cytochromes [120,121]. Mitochondrial dysfunction is an important feature of excessive FA influx, while increased FAO produces ROS and induces oxidative stress [122]. This imbalanced redox status can further promote damage to the mitochondrial membranes, leading to compromised liver function [123].…”

Metabolic Reprogramming is a Hallmark of Metabolism Itself

“…Metabolic reprogramming has been identified as occurring in alcoholic liver disease, aplastic anemia, inflammatory diseases, ischemic heart failure, ischemic‐reperfusion injury, amyotrophic lateral sclerosis, bacterial infections, Zika virus infection, and lung disease, among many others. [ 75,174–184 ]…”