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.

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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References

Bingle CD and Craven CJ (2004) Meet the relatives: a family of BPI‐ and LBP‐related proteins. Trends in Immunology 25(2): 53–55.

Bochkov VN, Oskolkova OV, Birukov KG et al. (2010) Generation and biological activities of oxidized phospholipids. Antioxidants and Redox Signaling 12(8): 1009–1059.

Chakraborty D, Banerjee S, Sen A et al. (2005) Leishmania donovani affects antigen presentation of macrophage by disrupting lipid rafts. Journal of Immunology 175(5): 3214–3224.

Cocquerel L, Voisset C and Dubuisson J (2006) Hepatitis C virus entry: potential receptors and their biological functions. Journal of General Virology 87(Pt 5): 1075–1084.

Cui D, Thorp E, Li Y et al. (2007) Pivotal advance: macrophages become resistant to cholesterol‐induced death after phagocytosis of apoptotic cells. Journal of Leukocyte Biology 82(5): 1040–1050.

Cvetanovic M, Mitchell JE, Patel V et al. (2006) Specific recognition of apoptotic cells reveals a ubiquitous and unconventional innate immunity. Journal of Biological Chemistry 281(29): 20055–20067.

de Chastellier C and Thilo L (2006) Cholesterol depletion in Mycobacterium avium‐infected macrophages overcomes the block in phagosome maturation and leads to the reversible sequestration of viable mycobacteria in phagolysosome‐derived autophagic vacuoles. Cellular Microbiology 8(2): 242–256.

Dennis EA, Deems RA, Harkewicz R et al. (2010) A mouse macrophage lipidome. Journal of Biological Chemistry 285(51): 39976–39985.

Dobson CB, Sales SD, Hoggard P, Wozniak M and Crutcher KA (2006) The receptor‐binding region of human apolipoprotein E has direct anti‐infective activity. Journal of Infectious Diseases 193(3): 442–450.

Gatfield J and Pieters J (2000) Essential role for cholesterol in entry of mycobacteria into macrophages. Science 288(5471): 1647–1650.

Glass CK and Saijo K (2010) Nuclear receptor transrepression pathways that regulate inflammation in macrophages and T cells. Nature Reviews Immunology 10(5): 365–376.

Halwani AE, Niven DF and Dunphy GB (2000) Apolipophorin‐III and the interactions of lipoteichoic acids with the immediate immune responses of Galleria mellonella. Journal of Invertebrate Pathology 76(4): 233–241.

Hamon Y, Broccardo C, Chambenoit O et al. (2000) ABC1 promotes engulfment of apoptotic cells and transbilayer redistribution of phosphatidylserine. Nature Cell Biology 2(7): 399–406.

Hayden JM, Brachova L, Higgins K et al. (2002) Induction of monocyte differentiation and foam cell formation in vitro by 7‐ketocholesterol. Journal of Lipid Research 43(1): 26–35.

Hochreiter‐Hufford A and Ravichandran KS (2013) Clearing the dead: apoptotic cell sensing, recognition, engulfment, and digestion. Cold Spring Harbor Perspectives in Biology 5(1). doi:10.1101/cshperspect.a008748.

Hoebe K, Georgel P, Rutschmann S et al. (2005) CD36 is a sensor of diacylglycerides. Nature 433(7025): 523–527.

Huynh MLN, Fadok VA and Henson PM (2002) Phosphatidylserine‐dependent ingestion of apoptotic cells promotes TGF‐β1 secretion and the resolution of inflammation. Journal of Clinical Investigation 109(1): 41–50.

Khovidhunkit W, Kim MS, Memon RA et al. (2004) Effects of infection and inflammation on lipid and lipoprotein metabolism: mechanisms and consequences to the host. Journal of Lipid Research 45(7): 1169–1196.

Kiss RS, Elliott MR, Ma Z, Marcel YL and Ravichandran KS (2006) Apoptotic cells induce a phosphatidylserine‐dependent homeostatic response from phagocytes. Current Biology 16(22): 2252–2258.

Knapp S, Matt U, Leitinger N and van der Poll T (2007) Oxidized phospholipids inhibit phagocytosis and impair outcome in gram‐negative sepsis in vivo. Journal of Immunology 178(2): 993–1001.

Leclair EE (2003) Four BPI (bactericidal/permeability‐increasing protein)‐like genes expressed in the mouse nasal, oral, airway and digestive epithelia. Biochemical Society Transactions 31(Pt 4): 801–805.

Mahley RW, Weisgraber KH and Huang Y (2009) Apolipoprotein E: structure determines function, from atherosclerosis to Alzheimer's disease to AIDS. Journal of Lipid Research 50 (Suppl.): S183–S188.

Mañes S, Del Real G and Martínez‐A C (2003) Pathogens: raft hijackers. Nature Reviews Immunology 3(7): 557–568.

Miller YI, Choi SH, Wiesner P et al. (2011) Oxidation‐specific epitopes are danger‐associated molecular patterns recognized by pattern recognition receptors of innate immunity. Circulation Research 108(2): 235–248.

Neculai D, Schwake M, Ravichandran M et al. (2013) Structure of LIMP‐2 provides functional insights with implications for SR‐BI and CD36. Nature 504(7478): 172–176.

Neyen C, Mukhopadhyay S, Gordon S and Hagemann T (2013) An apolipoprotein A‐I mimetic targets scavenger receptor A on tumor‐associated macrophages: a prospective anticancer treatment? OncoImmunology 2(6): e24461.

Piraino G, Cook JA, O'Connor M et al. (2006) Synergistic effect of peroxisome proliferator activated receptor‐gamma and liver X receptor‐alpha in the regulation of inflammation in macrophages. Shock 26(2): 146–153.

Pollard JW (2009) Trophic macrophages in development and disease. Nature Reviews Immunology 9(4): 259–270.

Poon IK, Lucas CD, Rossi AG and Ravichandran KS (2014) Apoptotic cell clearance: basic biology and therapeutic potential. Nature Reviews Immunology 14(3): 166–180.

Pratt CC and Weers PM (2004) Lipopolysaccharide binding of an exchangeable apolipoprotein, apolipophorin III, from Galleria mellonella. Biological Chemistry 385(11): 1113–1119.

Reddy ST, Navab M, Anantharamaiah GM and Fogelman AM (2014) Searching for a successful HDL‐based treatment strategy. Biochimica et Biophysica Acta 1841(1): 162–167.

Rodriguez NE, Gaur U and Wilson ME (2006) Role of caveolae in Leishmania chagasi phagocytosis and intracellular survival in macrophages. Cellular Microbiology 8(7): 1106–1120.

Schroder NW, Heine H, Alexander C et al. (2004) Lipopolysaccharide binding protein binds to triacylated and diacylated lipopeptides and mediates innate immune responses. Journal of Immunology 173(4): 2683–2691.

Schultz H and Weiss JP (2007) The bactericidal/permeability‐increasing protein (BPI) in infection and inflammatory disease. Clinica Chimica Acta 384(1–2): 12–23.

Seimon TA, Nadolski MJ, Liao X et al. (2010) Atherogenic lipids and lipoproteins trigger CD36‐TLR2‐dependent apoptosis in macrophages undergoing endoplasmic reticulum stress. Cell Metabolism 12(5): 467–482.

Seong SY and Matzinger P (2004) Hydrophobicity: an ancient damage‐associated molecular pattern that initiates innate immune responses. Nature Reviews Immunology 4(6): 469–478.

Serhan CN (2010) Novel lipid mediators and resolution mechanisms in acute inflammation: to resolve or not? American Journal of Pathology 177(4): 1576–1591.

Serhan CN and Savill J (2005) Resolution of inflammation: the beginning programs the end. Nature Immunology 6(12): 1191–1197.

Singh K, Chaturvedi R, Coppenhaver DH, Ananatharamaiah GM and Baron S (2011) The apolipoprotein E‐mimetic peptide COG112 inhibits NF‐kappaB signaling, proinflammatory cytokine expression, and disease activity in murine models of colitis. Journal of Biological Chemistry 286(5): 3839–3850.

Spann NJ and Glass CK (2013) Sterols and oxysterols in immune cell function. Nature Immunology 14(9): 893–900.

Sprong H, Suchanek M, van Dijk SM et al. (2006) Aberrant receptor‐mediated endocytosis of Schistosoma mansoni glycoproteins on host lipoproteins. PLoS Medicine 3(8): e253.

Stewart CR, Stuart LM, Wilkinson K et al. (2010) CD36 ligands promote sterile inflammation through assembly of a Toll‐like receptor 4 and 6 heterodimer. Nature Immunology 11(2): 155–161.

Tall A (1995) Plasma lipid transfer proteins. Annual Review of Biochemistry 64: 235–257.

Underhill DM (2007) Collaboration between the innate immune receptors dectin‐1, TLRs, and NODs. Immunological Reviews 219: 75–87.

Vanhamme L, Paturiaux‐Hanocq F, Poelvoorde P et al. (2003) Apolipoprotein L‐I is the trypanosome lytic factor of human serum. Nature 422(6927): 83–87.

Venkateswaran A, Laffitte BA, Joseph SB et al. (2000) Control of cellular cholesterol efflux by the nuclear oxysterol receptor LXR alpha. Proceedings of the National Academy of Sciences of the USA 97(22): 12097–12102.

Wang CQ, Yang CS, Yang Y et al. (2013) An apolipoprotein E mimetic peptide with activities against multidrug‐resistant bacteria and immunomodulatory effects. Journal of Peptide Science 19(12): 745–750.

Xu X, Remold HG and Caulfield JP (1993) Potential role for scavenger receptors of human monocytes in the killing of Schistosoma mansoni. American Journal of Pathology 142(3): 685–689.

Yao X, Vitek MP, Remaley AT and Levine SJ (2012) Apolipoprotein mimetic peptides: a new approach for the treatment of asthma. Frontiers in Pharmacology 3: 37.

Yu B, Hailman E and Wright SD (1997) Lipopolysaccharide binding protein and soluble CD14 catalyze exchange of phospholipids. Journal of Clinical Investigation 99(2): 315–324.

Zahringer U, Lindner B, Inamura S, Heine H and Alexander C (2008) TLR2 – promiscuous or specific? A critical re‐evaluation of a receptor expressing apparent broad specificity. Immunobiology 213(3–4): 205–224.

Further Reading

Bendelac A, Savage PB and Teyton L (2007) The biology of NKT cells. Annual Review of Immunology 25: 297–336.

Geissmann F, Gordon S, Hume DA, Mowat AM and Randolph GJ (2010) Unravelling mononuclear phagocyte heterogeneity. Nature Reviews Immunology 10(6): 453–460.

Helming L and Gordon S (2009) Molecular mediators of macrophage fusion. Trends in Cell Biology 19(10): 514–522.

Mantovani A and Sica A (2010) Macrophages, innate immunity and cancer: balance, tolerance, and diversity. Current Opinion in Immunology 22(2): 231–237.

Martinez FO and Gordon S (2014) The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Reports 6: 13

Mosser DM and Edwards JP (2008) Exploring the full spectrum of macrophage activation. Nature Reviews Immunology 8(12): 958–969.

Nature Reviews Immunology, Web Focus on Metabolism and Immunity (2011) http://www.nature.com/nri/focus/metabolism/index.html

Olefsky JM and Glass CK (2010) Macrophages, inflammation, and insulin resistance. Annual Review of Physiology 72: 219–246.

Qian BZ and Pollard JW (2010) Macrophage diversity enhances tumour progression and metastasis. Cell 141(1): 39–51.

Steinberg D (2007) The Cholesterol Wars, Elsevier Ltd. 227 pp. New York, NY: Academic Press. ISBN 978‐0123739797.

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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. http://www.els.net [doi: 10.1002/9780470015902.a0021029.pub2]