For decades, the activation of inflamma-tory responses by lipids has interested in-vestigators working on a wide variety ofhuman diseases. Exogenous lipids, derivedfrom the walls of microbial pathogens,and endogenous lipids, generated fromthe oxidation of fatty acids and choles-terol, can both activate cells of the im-mune system and stimulate potentpro-inflammatory events. The mecha-nisms that hosts use to restrain the inflam-matory response and restrict its temporalcourse have been less well explored. Theabsence of these restraints can lead tochronic inflammatory conditions, ofwhich several, including arthritis,Alzheimer disease and atherosclerosis, arecommon afflictions of aging. The recentidentification of a class of aspirin-triggeredlipid molecules called resolvins, with re-markable anti-inflammatory properties,indicates that lipid pathways may havemuch to contribute to the resolutionphase of inflammation1. In this issue,Joseph et al. identify a new pathway bywhich both endogenous lipids and phar-maceutical compounds can restrain in-flammation, through the activation of aclass of nuclear hormone receptors calledliver X receptors (LXRs; ref.2).

Although originally identified as liver-enriched transcription factors, the LXRsare now being intensely studied in themacrophage, a key effector cell of both theinnate and adaptive immune responses.Macrophages act as the first line of defenseagainst noxious materials, including oxi-dized lipids. The internalization of these

oxidized lipids, as well as intracellular en-zymatic modification of accumulated cho-lesterol, generate ligands that activateseveral nuclear hormone transcription fac-tors3. The LXRs, with their binding partnerretinoid X receptor (RXR), are activated byoxysterols such as the naturally occurring22(R)-hydroxycholesterol3. In addition,there are several highly specific syntheticligands used to study LXR function in cel-lular and whole-animal experiments.LXRs are now known to regulate a numberof genes involved in lipid metabolism, in-cluding those encoding the cholesteroltransporter ABCA1, plasma phospholipidtransfer protein, steroyl-CoA desaturaseand apolipoproteins E and CII (ref. 4–10).

The authors used microarray transcrip-tional profiling to screen globally for LXR-responsive genes. They found that LXRagonists inhibited expression of a clusterof genes involved in the innate immuneresponse of activated macrophages. Thegenes encoding these inflammatory medi-ators, including inducible nitric oxide syn-thase (iNOS), cyclooxygenase-2 (COX-2)and several cytokines and chemokines,were the most highly repressed genes onthe microarray. This indicated a role forLXRs in limiting macrophage-generatedinflammation. In a series of experimentsusing both acute and chronic models ofinflammation, Joseph et al. confirmed thishypothesis by showing that LXR ligands

induce broad anti-inflammatory responsesin vitro and in vivo.

Joseph et al. performed in vitro assaysshowing that LXR ligands inhibited theexpression of iNOS and COX-2 in wildtype, but not LXR-α/β–/–, macrophages thathad been primed with whole Gram-nega-tive bacteria or its component lipopolysac-charide (LPS). The anti-inflammatoryeffect of LXR agonists was dose depen-dent, occurring over the same range ofconcentrations that increase ABCA1 trans-porter expression and cellular cholesterolefflux. In a macrophage cell line, a LXR ag-onist reduced expression of reporter con-structs driven by the promoters of thegenes encoding iNOS and COX-2, point-ing to repression of transcription as a com-mon mechanism of LXR action. Like thoseof many pro-inflammatory genes, thesepromoters contain binding sites for thetranscription factors NFκB and activatorprotein-1 (AP-1). Using minimal promoterconstructs, the authors showed that LXRagonists repressed NFκB-driven reporter-gene expression but did not affect AP-1-driven gene expression. Thus, LXRagonists may exert broad anti-inflamma-tory effects by repressing several NFκB tar-get genes in activated macrophages,including those encoding interleukin (IL)-1β, monocyte chemotactic protein (MCP)-1, and IL-6.

To confirm the anti-inflammatory ac-tion of LXR in vivo, Joseph et al. used threeestablished mouse models of inflamma-tion: LPS-induced sepsis, acute contactdermatitis of the ear, and chronic athero-

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used to selectively modulate angiogen-esis and lymphangiogenesis, restoringtissue vascularization and homeostasisand also inhibiting unwanted lymph−angiogenic processes during tumorige-nesis andother disorders.

1. Witte, M.H., Way, D.L., Witte, C.L. & Bernas, M.Lymphangiogenesis: mechanisms, significanceand clinical implications. EXS 79, 65–112 (1997).

2. Alitalo, K. & Carmeliet, P. Molecular mechanismsof lymphangiogenesis in health and disease.Cancer Cell 1, 219–227 (2002).

3. Abtahian, F. et al. Regulation of blood and lym-phatic vascular separation by signaling proteinsSLP-76 and Syk. Science 299, 247–251 (2002).

4. Clements, J.L. et al. Fetal hemorrhage andplatelet dysfunction in SLP-76-deficient mice. J.Clin. Invest. 103, 19–25 (1999).

5. Myung, P.S. et al. Differential requirement for

SLP-76 domains in T cell development and func-tion. Immunity 15, 1011–1026 (2001).

6. Turner, M., Schweighoffer, E., Colucci, F., DiSanto, J.P. & Tybulewicz, V.L. Tyrosine kinaseSYK: essential functions for immunoreceptor sig-nalling. Immunol. Today 21, 148–154 (2000).

7. Sabin, F. On the origin of the lymphatic systemfrom the veins and the development of thelymph hearts and thoracic duct in the pig. Am. J.Anat. 4, 367–389 (1901).

8. Oliver, G. & Detmar, M. The rediscovery of thelymphatic system: old and new insights into thedevelopment and biological function of the lym-phatic vasculature. Genes Dev. 16, 773–783(2002).

9. Wigle, J.T. & Oliver, G. Prox1 function is re-quired for the development of the murine lym-phatic system. Cell 98, 769–778 (1999).

10. Yanagi, S. et al. Syk expression in endothelialcells and their morphologic defects in embryonicSyk-deficient mice. Blood 98, 2869–2871 (2001).

11. Rafii, S., Lyden, D., Benezra, R., Hattori, K. &

Heissig, B. Vascular and haematopoietic stemcells: novel targets for anti-angiogenesis ther-apy? Nat. Rev. Cancer 2, 826–835 (2002).

12. Takakura, N. et al. A role for hematopoietic stemcells in promoting angiogenesis. Cell 102,199–209 (2000).

13. Lyden, D. et al. Impaired recruitment of bone-marrow-derived endothelial and hematopoieticprecursor cells blocks tumor angiogenesis andgrowth. Nat. Med. 7, 1194–1201 (2001).

14. Swartz, M.A. & Skobe, M. Lymphatic function,lymphangiogenesis, and cancer metastasis.Microsc. Res. Techniq. 55, 92–99 (2001).

1Cornell University Medical CollegeNew York, New York, USAEmail: mihaela.skobe@mssm.edu2Mount Sinai School of MedicineNew York, New York, USAEmail: srafii@med.cornell.edu

eLiXiRs for restraining inflammationNew data implicate the LXRs, a class of nuclear hormone receptors, in reducing inflammation. When activated,

these receptors ease inflammation in three mouse models. The results are relevant to atherosclerosis, Alzheimerdisease, sepsis and other inflammatory disorders (pages 213–219).

MASON W. FREEMAN & KATHRYN J. MOORE

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sclerotic inflammation of the artery wall.These disease models differ in the contri-butions that leukocytes other thanmacrophages make to the inflammatoryprocess, with neutrophils playing a greaterrole in dermatitis, the more acute inflam-matory disorder. Despite these differences,LXR activation reduced inflammation andpro-inflammatory gene expression in allthree settings. In the sepsis model, cy-tokine production increased in the ab-sence of LXR activation. In the dermatitismodel, a pronounced reduction in edemaand leukocyte infiltration occurred in theears of mice treated with an LXR agonist.Further work will be required to determinewhether these effects depend on direct ac-tivation of anti-inflammatory pathways inthe neutrophil.

In mice with established atheroscleroticvascular disease, a three-day treatment

with LXR agonists reduced the expressionof matrix metalloproteinase-9, an extracel-lular matrix-degrading protease impli-cated in plaque instability. The authorsdid not see any effects of LXR agonists onvascular iNOS or MCP-1 expression in theatherosclerosis model. Given the short du-ration of treatment and the sporadic na-ture of atherosclerotic lesions, however,this is not entirely surprising. LXR activa-tion can reduce atherosclerosis in mousemodels of the disease11,12, but the mecha-nism of that effect has not been defined.These new data, in conjunction with pre-vious studies of LXR-mediated activationof ABCA1-dependent cholesterol ef-flux10,13, suggest that LXR agonists engagea two-pronged attack that reduces athero-sclerosis by removing cholesterol frommacrophages and decreasing their inflam-matory repertoire.

Unfortunately, the use of LXR agoniststo treat human atherosclerosis is not in theimmediate offing. LXR agonists induceseveral genes involved in lipid metabolism,resulting in marked elevations in rodentserum triglyceride levels and sufficient ac-cumulation of fat in the liver to cause afatty infiltration called steatosis14. Until therelevance of these issues to human biologyis resolved or more selective compoundsare generated, the eLiXiRs will remain lab-oratory concoctions, used primarily to illu-minate the complexity of genetic traffic atthe intersection of lipids and inflamma-tion. The work of Joseph et al. contributesto the emerging evidence that this traffic isnot confined to a one-way street.

1. Serhan, C.N. et al. Resolvins: a family of bioactiveproducts of omega-3 fatty acid transformation cir-cuits initiated by aspirin treatment that counterproinflammation signals. J. Exp. Med. 196,1025–1037 (2002).

2. Joseph, S.B., Castrillo, A., Laffitte, B.A., Mangelsdorf,D.J. & Tontonoz, P. Reciprocal regulation of inflam-mation and lipid metabolism by LXRs. Nat. Med. 9,213–219 (2003).

3. Repa, J.J. & Mangelsdorf, D.J. The role of orphan nu-clear receptors in the regulation of cholesterol home-ostasis. Annu. Rev. Cell. Dev. Biol. 16, 459–481 (2000).

4. Laffitte, B.A. et al. LXRs control lipid-inducible expres-sion of the apolipoprotein E gene in macrophagesand adipocytes. Proc. Natl. Acad. Sci. USA 98,507–512 (2001).

5. Joseph, S.B. et al. Direct and indirect mechanisms forregulation of fatty acid synthase gene expression byliver X receptors. J. Biol. Chem. 277, 11019–11025(2002).

6. Cao, G. et al. Phospholipid transfer protein is regu-lated by liver X receptors in vivo. J. Biol. Chem. 277,39561–39565 (2002).

7. Costet, P., Luo, Y., Wang, N. & Tall, A.R. Sterol-de-pendent transactivation of the ABC1 promoter by theliver X receptor/retinoid X receptor. J. Biol. Chem.275, 28240–28245 (2000).

8. Mak, P.A. et al. Regulated expression of theapolipoprotein E/C-I/C-IV/C-II gene cluster in murineand human macrophages. A critical role for nuclearliver X receptors α and β. J. Biol. Chem. 277,31900–31908 (2002).

9. Repa, J.J. et al. Regulation of mouse sterol regulatoryelement-binding protein-1c gene (SREBP-1c) byoxysterol receptors, LXR-α and LXR-β. Genes Dev. 14,2819–2830 (2000).

10. Schwartz, K., Lawn, R.M. & Wade, D.P. ABC1 geneexpression and ApoA-I-mediated cholesterol effluxare regulated by LXR. Biochem. Biophys. Res. Commun.274, 794–802 (2000).

11. Tangirala, R.K. et al. Identification of macrophageliver X receptors as inhibitors of atherosclerosis. Proc.Natl. Acad. Sci. USA 99, 11896–11901 (2002).

12. Joseph, S.B. et al. Synthetic LXR ligand inhibits the de-velopment of atherosclerosis in mice. Proc. Natl. Acad.Sci. USA 99, 7604–7609 (2002).

13. Venkateswaran, A. et al. Control of cellular cholesterolefflux by the nuclear oxysterol receptor LXR-α. Proc.Natl. Acad. Sci. USA 97, 12097–12102 (2000).

14. Schultz, J.R. et al. Role of LXRs in control of lipogene-sis. Genes Dev. 14, 2831–2838 (2000).

Lipid Metabolism UnitDepartment of MedicineMassachusetts General Hospital and Harvard Medical SchoolBoston, Massachusetts, USAEmail: freeman@frodo.mgh.harvard.edu

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Fig. 1 LXRs regulate inflammation and lipid metabolism. LXR activation influences dual pathwaysthat reduce chronic inflammation involving macrophages. Macrophages internalize oxidized lowdensity lipoproteins (OxLDL) through a family of scavenger receptors (for example, class A scavengerreceptor (SR-A) and CD36). Oxysterols derived from these lipoproteins, cholesterol modified by in-tracellular enzymes, or synthetic LXR agonists serve as ligand activators of the heterodimeric nuclearhormone LXR-RXR. This results in upregulation of genes that accelerate lipid removal frommacrophages (such as the genes encoding ABCA1 and apolipoprotein E). Joseph et al. report that LXRactivation can also repress expression of a set of pro-inflammatory genes (for example, those encod-ing COX-2 and IL-6). These pro-inflammatory genes can be activated by both endogenous and mi-crobial lipids (such as bacterial LPS). These dual effects of LXR activation would be expected to lessenthe formation of atherosclerotic plaques, a finding confirmed in atherosclerosis-prone mice treatedwith LXR agonists. The authors also show that LXR agonists reduce inflammation in LPS-induced sep-sis and contact dermatitis; likely though repression of the pro-inflammatory pathways, and not in-duction of lipid efflux.

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