Neutrophil TLR2 signaling promotes lipid accumulation and vascular plaque growth

Abstract

Neutrophils are short-lived cells that are produced by the billions every day to circulate throughout the body and surveil all tissues. They are a key component of the innate immune system that play essential roles in antimicrobial immunity, but can also instigate sterile inflammatory diseases like gout and cancer. Immunometabolic paradigms that were developed by studying T cells and macrophages establish that cellular metabolic programming dictates immune function. Neutrophils have long been known as glucose-reliant and highly glycolytic. But surprising neutrophil heterogeneity has recently been described, and roles for lipids have been reported in both granulopoiesis and mature neutrophil effector function. Therefore, we set out to uncover how neutrophils acquire lipids from their environment and how this influences their functionality in the context of lipotoxicity. We found that neutrophils take up both free fatty acids and complex lipoproteins, but that their uptake is regulated through different signaling pathways. Neutrophil lipoprotein uptake is inducible by certain TLR2 signals, and this causes neutrophils to depolymerize their actin fibers and stop moving. Using a mouse model of atherosclerosis, we show that neutrophils in the plaque are lipid-laden and that neutrophil-deficient mice are protected from atherosclerotic plaque growth. Lipoprotein uptake causes neutrophils to recruit macrophages, conditional ablation of TLR2 on neutrophils prevents their lipid uptake and storage, and these mice are also protected against atherosclerosis. Our work highlights an important understudied role for lipids in neutrophil biology, and the importance of studying different lipid classes and different signaling pathways in neutrophils as compared to other myeloid populations.