Macrophages in Lipid and Immune Homeostasis

Abstract

Many components of the immune system play diverse roles in lipid metabolism and vice versa. Macrophage immune functions, including pathogen clearance and apoptotic cell removal, depend on recognition of lipid ligands by surface and intracellular immune receptors and secreted lipid‐binding molecules. Engagement of lipid receptors triggers an immune response, which is accompanied by de novo synthesis of bioactive lipids that help resolve inflammation. Oxidised lipids, byproducts of the oxidative burst, activate nuclear receptors, which not only orchestrate lipid homoeostasis but also cross‐regulate NFκB‐driven immune responses. Activation of macrophages leads to cytokine production and induction of the acute phase response, accompanied by systemic lipid changes. Lipoproteins and their components, as well as lipid transport molecules, are emerging as novel actors in innate immune defence. Key Concepts: Macrophages interact with cells and organs involved in lipid uptake, distribution and storage. The immune repertoire of macrophages and other immune cells includes a range of surface and intracellular lipid sensors that detect self and nonself lipids. Phagocytosis of pathogens and apoptotic cells is modulated by lipid ligands. The oxidative burst accompanying the immune response oxidises lipids and generates secondary messengers. The intracellular cholesterol content of macrophages is sensed by the endoplasmic reticulum and by lipid‐binding nuclear receptors. Lipid‐activated nuclear receptors including PPARs and LXRs adjust the transcriptome of macrophages and can modulate proinflammatory transcription factors such as NFκB. Systemic or chronic immune activation is accompanied by secretory changes in the liver, a process called acute phase response. Acute phase response proteins contribute to lipid scavenging in the circulation. Apolipoproteins, transport molecules that carry lipids through the circulation, show a versatile antimicrobial, anti‐inflammatory and antitumour potential for therapy.

Peroxisome-Mediated Metabolism Is Required for Immune Response to Microbial Infection

“…Increasing numbers of important metabolic functions are being attributed to peroxisomes in addition to their long recognized roles in anabolic and catabolic reactions of lipid metabolism (Wanders and Waterham, 2006;Waterham et al, 2016). Lipids are emerging as factors involved in innate immune defense, as systemic lipid changes accompany the acute phase of the macrophage response, and the de novo synthesis of bioactive lipids is needed for the resolution of inflammation (Neyen and Gordon, 2014). Our findings identified a previously unexplored function for peroxisomes in innate immunity.…”

“…The changes in ROS and RNS in Pex5-i and Pex7-i cells are most likely the result of abnormal peroxisomal function, perhaps with respect to the peroxisomes' prominent role in lipid metabolism. Lipid has been shown to signal RNS production during infection (Anes et al, 2003), and oxidized lipids, byproducts of the phagosome oxidative burst, activate nuclear receptors that orchestrate lipid homeostasis and cross regulate NF-kB-driven immune responses (Neyen and Gordon, 2014). The deregulation in ROS and RNS homeostasis that is observed upon infection of Pex5-i and Pex7-i cells implicates peroxisomes in the host response to infection through their regulation of the actin network to mediate phagocytosis and through their mediation of intracellular signaling pathways.…”

“…Peroxisomes function in lipid metabolism and the detoxification of reactive oxygen species (ROS) (Nguyen et al, 2008;Wanders and Waterham, 2006). As lipids and ROS have recently emerged as important signaling factors in cellular and systemic immune responses (Nathan and Shiloh, 2000;Neyen and Gordon, 2014), we investigated a role for peroxisomes in the innate immune response using Drosophila cells and animals in which two key peroxin genes, Pex5 and Pex7, were impaired. We found a previously unknown role for peroxisomes in microbe engulfment and host defense by macrophages.…”

Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight

“…As a major component of cell membranes, lipids regulate immune cell signalling and function by affecting membrane fluidity 111 . Lipids and certain lipoproteins also serve as ligands for various immune receptors to mediate immune cell activation and phagocytosis 132,133 . Other lipid-mediated mechanisms such as regulation of gene transcription and eicosanoid production have also been proposed to affect immune function 134 .…”

Macrophage Heterogeneity in the Immunopathogenesis of Tuberculosis

“…Possible mechanisms include mobilization from lipid stores, endocytosis and deposition in macrophages, enhanced synthesis, locally and systemically, and/or failure to degrade accumulated lipids in macrophages. Macrophage foam cells form readily after uptake of various protein-bound lipids by a range of scavenger receptors, e.g., SR-A, CD36 and LDL receptors (Neyen and Gordon, 2014 ). Lipid droplets arise by synthesis and export from the endoplasmic reticulum to the cytosol, before becoming bound by vesicle membranes (Figure 2 ).…”