Macrophages in Lipid and Immune Homeostasis


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.

Keywords: macrophage; innate immunity; metabolism; lipoprotein(s); nuclear receptor(s); oxidised lipid(s); apolipoprotein mimetic(s)

Figure 1.

Macrophages are central to lipid and immune homoeostasis. Bone marrow‐derived monocytes can leave the circulation by transmigration through the vascular endothelium. Cytokines, modified lipids and adipokines (leptin) all activate the endothelium to express monocyte chemoattractants (IL‐8 and MCP‐1) and adhesion molecules (ICAM, VCAM and E‐selectin). Extravasated monocytes become tissue macrophages, Kupffer cells in the liver, adipose tissue macrophages or lamina propria macrophages in the small intestine, and cholesterol loaded foam cells in the subendothelial space, in the case of atherosclerosis. The adipocyte secretome includes lipids generate during lipolysis (FAs, cholesterol, retinol, prostanoids and steroid hormones) which are potential immunomodulators, adipokines (anti‐inflammatory adiponectin and proinflammatory leptin), cytokines (TNFα and IL‐6) which contribute to the generalised inflammation associated with obesity, as well as chemokines (MCP‐1) and growth factors (MIF and M‐CSF) which drive monocyte infiltration and differentiation into activated macrophages. Both macrophage and adipocyte‐derived TNFα, IL‐1β and IL‐6 induce the acute phase response in the liver. The resulting changes in the hepatocyte secretome impact on cholesterol metabolism and reverse cholesterol transport from the periphery and induce lipolysis in the adipose tissue. Enterocytes absorb dietary lipids from the intestines and release them into the circulation. Both dietary and bacterial saturated FAs can activate the innate immune system via Toll‐like receptors. PUFAs are precursors for eicosanoid biosynthesis and can act locally on the inflammatory response generated by DCs and possibly lamina propria macrophages sampling the gut contents. Dysregulation of this balance leads to chronic states like inflammatory bowel disease. Microglia in the brain secrete neurotrophins to maintain neuronal homoeostasis, but chronic microglial activation can lead to inflammatory cytokine production and oxidative stress which contributes to neurodegeneration. Chronic inflammation is one factor driving mutagenesis. Tumour cells and tumour‐associated macrophages (TAMs) cross‐talk via CSF‐1, chemokines and lipid mediators including LPA. TAMs contribute to angiogenesis and progression to metastasis.

Figure 2.

Modulation of phagocytic mechanisms by lipoproteins. (a) Recognition of pathogens by Toll‐like receptors (TLRs) activates NFκB signalling, which results in release of cytokines and reactive oxygen species (ROS). Local ROS secretion oxidises membrane phospholipids and lipoproteins, which can both compete with bacterial recognition by TLRs or clearance by scavenger receptors. (b) Inflammatory cytokine release and septic shock are avoided when LPS or LTA is shuttled on lipoproteins. These entities are cleared via lipoprotein receptors on hepatocytes and do not induce inflammation. (c) Schistosoma mansoni eggs carry a LDL coat to evade recognition by antibodies. Local ROS oxidises LDL and enables macrophages to remove the oxLDL coat via scavenger receptors. Naked eggs can then be attacked by the immune system (Xu et al., ). (d) Normally innocuous lipoproteins carrying parasite lipids (as shown for glycosylphosphatidylinositol (GPI)‐anchored surface antigens from S. mansoni and Trypanosoma brucei), are tagged for recognition by parasite‐specific antibodies and undergo aberrant immune clearance via Fc receptors (Sprong et al., ). (e) Lipid rafts are entry points for intracellular pathogens which avoid subsequent phagolysosome fusion and survive in the cytoplasm, without appropriate inflammatory response or degradation and antigen presentation.

Figure 3.

Phagocytic clearance of apoptotic cells induces changes in cholesterol homoeostasis. Dying neutrophils contain a range of oxidised membrane lipids (oxidised phospholipids (oxPS and oxPC), cholesterol and cholesteryl esters, oxysterols) which are recognised by scavenger receptors on the phagocyte. After ingestion, lysosomal hydrolases release oxysterols, FAs and oxidised phospholipids as well as free cholesterol (FC) from cholesteryl esters (CE). Free cholesterol induces stress and eventually apoptosis, which is prevented by re‐esterification into cholesteryl esters by acyl‐coenzyme A: cholesterol acyltransferase in the ER. FAs and oxysterols released during digestion in lysosomes transfer to the nucleus where they activate their respective nuclear receptors, PPAR and LXR. PPARs bind to PPRE (PPAR responsive elements) in the promoter region of LXRs and increase LXR transcription. Oxysterol activation of LXR drives ABCA1 and SRBI expression which then efflux surplus cholesteryl esters to lipid‐poor apo A‐I and to HDL for reverse transport to the liver and biliary excretion.



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Neyen, Claudine D, and Gordon, Siamon(Jul 2014) Macrophages in Lipid and Immune Homeostasis. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0021029.pub2]