Macrophages in Lipid and Immune Homeostasis

Claudine D Neyen, Oxford University, Oxford, UK
Siamon Gordon, Oxford University, Oxford, UK

Published online: December 2008

DOI: 10.1002/9780470015902.a0021029

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, are regulated by lipids but also generate effectors that impact on lipid homeostasis. Oxidized lipids, byproducts of the oxidative burst, activate nuclear receptors, which not only orchestrate lipid homeostasis but also cross-regulate NFB-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.

Keywords: macrophage; innate immunity; lipoprotein(s); nuclear receptor(s); oxidized lipid(s)

Figure 1. Macrophages are central to lipid and immune homeostasis. (a) 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, MCP-1) and adhesion molecules (ICAM, VCAM, 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 sub-endothelial space, in the case of atherosclerosis. (b) The adipocyte secretome includes lipids generate during lipolysis (FAs, cholesterol, retinol, prostanoids, steroid hormones) which are potential immunomodulators, adipokines (anti-inflammatory adiponectin and pro-inflammatory leptin), cytokines (TNF, IL-6) which contribute to the generalized inflammation associated with obesity, as well as chemokines (MCP-1) and growth factors (MIF, M-CSF) which drive monocyte infiltration and differentiation into activated macrophages. (c) Both macrophage and adipocyte-derived TNF, IL-1 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. (d) 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 dendritic cells and possibly lamina propria macrophages sampling the gut contents. Dysregulation of this balance leads to chronic states like inflammatory bowel disease.
Figure 2. Phagocytic mechanisms and their modulation by lipids. (a) Recognition of pathogens induces the TLR pathway and NFB transcriptional activation, which results in release of cytokines and reactive oxygen species (ROS). Local ROS secretion oxidizes membrane phospholipids and lipoproteins, which can both compete with or enhance bacterial recognition and/or clearance. (b) Pathogens coated with oxidized LDL are taken up via scavenger receptors. (c) Lipoproteins shuttling LPS or LTA are cleared via lipoprotein receptors and avoid induction of inflammation. (d) Lipoproteins containing GPI-anchored parasitic surface proteins are coated with parasite-specific antibodies and cleared by Fc receptors. (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 homeostasis. Dying neutrophils contain a range of oxidized membrane lipids (oxidized phospholipids (oxPS, oxPC), cholesterol and cholesteryl esters, oxysterols) which are recognized by scavenger receptors on the phagocyte. After ingestion, lysosomal hydrolases release oxysterols, FAs and oxidized 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. Therewhile, FAs and oxysterols 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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Related Sub-Topics:

Immunoregulation | Cells of the Immune System | Lipids: Structure, Function, Metabolism
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Article Title: Macrophages in Lipid and Immune Homeostasis
 
How to Cite close
Neyen, Claudine D, and Gordon, Siamon(Dec 2008) Macrophages in Lipid and Immune Homeostasis. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0021029]