Peroxisome proliferator-activated receptor α
and γ agonists differently regulate classical and
alternative macrophage activation

• Authors: Erja-Leena Paukkeri , Antti Pekurinen , Eeva Moilanen
• Languages of publication: EN

Abstracts

EN

Peroxisome proliferator-activated receptor
(PPAR) agonists, fibrates and thiazolidinediones, are
commonly used drugs in the treatment of dyslipidemia and
diabetes. Their targets, PPARα and PPARγ, have also been
shown to have a role in the regulation of inflammatory
responses linking metabolism and inflammation. In
the present study we investigated the effects of PPAR
agonists on macrophage activation. In addition to the
proinflammatory classical activation, we also focused
on interleukin (IL) 4 and 13 -induced alternative
activation which is a significant macrophage phenotype
in tissue repairing processes and in fibrosing diseases.
PPARα agonists GW7647 and fenofibrate as well as PPARγ
agonist GW1929 inhibited lipopolysaccharide-induced
classical macrophage activation and production of the
characteristic biomarkers of this phenotype, i.e. IL-6 and
nitric oxide, in murine J774 macrophages. Remarkably,
the PPARα agonists also inhibited IL-4 and IL-13 –induced
expression of alternative activation markers arginase-1,
fizz1 and mannose receptor 1 whereas the PPARγ agonist
GW1929 enhanced their expression in J774 macrophages.
The PPARα agonists GW7647 and fenofibrate also
attenuated the production of alternative activation
markers chemokine (C-C motif) ligand 13 and plateletderived
growth factor in human THP-1 macrophages.
The present findings show that PPARα and PPARγ agonists
differently regulate classical and alternative macrophage
phenotypes. Furthermore, PPARα activation was
introduced as a novel concept to down-regulate alternative
macrophage activation indicating that PPARα agonists
have therapeutic potential in conditions associated with aberrant alternative macrophage activation such as
fibrosing diseases.

Keywords

EN

Macrophage polarization; peroxisomeproliferator-activated receptor; fibrosis

• Publisher: De Gruyter Open
• Journal: Immunometabolism
• Year: 2015
• Volume: 2
• Issue: 1

Dates

received

2 - 3 - 2015

online

21 - 4 - 2015

accepted

23 - 3 - 2015

Contributors

author

Erja-Leena Paukkeri

• The Immunopharmacology
  Research Group, University of Tampere School of Medicine and
  Tampere University Hospital, Tampere, Finland

author

Antti Pekurinen

• The Immunopharmacology
  Research Group, University of Tampere School of Medicine and
  Tampere University Hospital, Tampere, Finland

author

Eeva Moilanen

• The Immunopharmacology
  Research Group, University of Tampere School of Medicine and
  Tampere University Hospital, Tampere, Finland

References

• [1] Ginhoux F., Jung S., Monocytes and macrophages:Developmental pathways and tissue homeostasis, Nat. Rev.Immunol., 2014, 14, 392-404[WoS][Crossref]
• [2] Van Dyken S.J., Locksley R.M., Interleukin-4- and interleukin-13-mediated alternatively activated macrophages: Roles inhomeostasis and disease, Annu. Rev. Immunol., 2013, 31,317-343[Crossref][PubMed]
• [3] Wynn T.A., Chawla A., Pollard J.W., Macrophage biology indevelopment, homeostasis and disease, Nature, 2013, 496,445-455[WoS]
• [4] Martinez F.O., Helming L., Gordon S., Alternative activation ofmacrophages: An immunologic functional perspective, Annu.Rev. Immunol., 2009, 27, 451-483[Crossref][PubMed][WoS]
• [5] Karp C.L., Murray P.J., Non-canonical alternatives: What amacrophage is 4, J. Exp. Med., 2012, 209, 427-431[WoS]
• [6] Murray P.J., Wynn T.A., Protective and pathogenic functions ofmacrophage subsets, Nat. Rev. Immunol., 2011, 11, 723-737[PubMed][Crossref]
• [7] Wynn T.A., Barron L., Macrophages: Master regulators ofinflammation and fibrosis, Semin. Liver Dis., 2010, 30, 245-257[Crossref][PubMed][WoS]
• [8] Munder M., Arginase: An emerging key player in themammalian immune system, Br. J. Pharmacol., 2009, 158,638-651
• [9] Iwamoto T., Okamoto H., Kobayashi S., Ikari K., Toyama Y.,Tomatsu T., et al., A role of monocyte chemoattractant protein-4(MCP-4)/CCL13 from chondrocytes in rheumatoid arthritis, FEBSJ., 2007, 274, 4904-4912
• [10] Wilson M.S., Mentink-Kane M.M., Pesce J.T., Ramalingam T.R.,Thompson R., Wynn T.A., Immunopathology of schistosomiasis,Immunol. Cell Biol., 2007, 85, 148-154[WoS]
• [11] Horsnell W.G., Brombacher F., Genes associated withalternatively activated macrophages discretely regulatehelminth infection and pathogenesis in experimental mousemodels, Immunobiology, 2010, 215, 704-708[WoS]
• [12] van Bon L., Cossu M., Radstake T.R., An update on an immunesystem that goes awry in systemic sclerosis, Curr. Opin.Rheumatol., 2011, 23, 505-510[PubMed][Crossref]
• [13] Mathai S.K., Gulati M., Peng X., Russell T.R., Shaw A.C.,Rubinowitz A.N., et al., Circulating monocytes from systemicsclerosis patients with interstitial lung disease show anenhanced profibrotic phenotype, Lab. Invest., 2010, 90,812-823[WoS]
• [14] Odegaard J.I., Ricardo-Gonzalez R.R., Goforth M.H., Morel C.R.,Subramanian V., Mukundan L., et al., Macrophage-specificPPARgamma controls alternative activation and improvesinsulin resistance, Nature, 2007, 447, 1116-1120[WoS]
• [15] Bouhlel M.A., Derudas B., Rigamonti E., Dievart R.,Brozek J., Haulon S., et al., PPARgamma activation primeshuman monocytes into alternative M2 macrophages withanti-inflammatory properties, Cell. Metab., 2007, 6, 137-143[Crossref]
• [16] Fruchart J.C., Peroxisome proliferator-activated receptor-alpha(PPARα): At the crossroads of obesity, diabetes and cardiovasculardisease, Atherosclerosis, 2009, 205, 1-8[WoS]
• [17] Paukkeri E.L., Leppanen T., Lindholm M., Yam M.F., AsmawiM.Z., Kolmonen A., et al., Anti-inflammatory properties of adual PPARgamma/alpha agonist muraglitazar in in vitro and invivo models, Arthritis Res. Ther., 2013, 15, R51[Crossref][WoS]
• [18] Paukkeri E.L., Leppänen T., Sareila O., Vuolteenaho K.,Kankaanranta H., Moilanen E., PPARα agonists inhibitnitric oxide production by enhancing iNOS degradation inLPS-treated macrophages, Br J Pharmacol, 2007, 152, 1081-1091
• [19] Mattace Raso G., Russo R., Calignano A., Meli R., Palmitoylethanolamidein CNS health and disease, Pharmacol. Res., 2014,86, 32-41[PubMed][Crossref]
• [20] Green L.C., Wagner D.A., Glogowski J., Skipper P.L., WishnokJ.S., Tannenbaum S.R., Analysis of nitrate, nitrite, and [15N]nitrate in biological fluids, Anal Biochem, 1982, 126, 131-138
• [21] Bradford M.M., A rapid and sensitive method for thequantitation of microgram quantities of protein utilizingthe principle of protein-dye binding, Anal Biochem, 1976, 7,248-254[Crossref]
• [22] Martinez F.O., Gordon S., Locati M., Mantovani A.,Transcriptional profiling of the human monocyte-tomacrophagedifferentiation and polarization: New moleculesand patterns of gene expression, J. Immunol., 2006, 177,7303-7311
• [23] Odegaard J.I., Ricardo-Gonzalez R.R., Goforth M.H., Morel C.R.,Subramanian V., Mukundan L., et al., Macrophage-specificPPARgamma controls alternative activation and improvesinsulin resistance, Nature, 2007, 447, 1116-1120[WoS]
• [24] Odegaard J.I., Ricardo-Gonzalez R.R., Red Eagle A., Vats D.,Morel C.R., Goforth M.H., et al., Alternative M2 activation ofkupffer cells by PPARdelta ameliorates obesity-induced insulinresistance, Cell. Metab., 2008, 7, 496-507[Crossref]
• [25] Christmann R.B., Hayes E., Pendergrass S., Padilla C., FarinaG., Affandi A.J., et al., Interferon and alternative activationof monocyte/macrophages in systemic sclerosis-associatedpulmonary arterial hypertension, Arthritis Rheum., 2011, 63,1718-1728[WoS]
• [26] Hasegawa M., Fujimoto M., Kikuchi K., Takehara K., Elevatedserum levels of interleukin 4 (IL-4), IL-10, and IL-13 in patientswith systemic sclerosis, J. Rheumatol., 1997, 24, 328-332
• [27] Homer R.J., Herzog E.L., Recent advances in pulmonary fibrosis:Implications for scleroderma, Curr. Opin. Rheumatol., 2010, 22,683-689[Crossref]
• [28] Hardie W.D., Glasser S.W., Hagood J.S., Emerging concepts inthe pathogenesis of lung fibrosis, Am. J. Pathol., 2009, 175,3-16[WoS]
• [29] Aliprantis A.O., Wang J., Fathman J.W., Lemaire R., DorfmanD.M., Lafyatis R., et al., Transcription factor T-bet regulates skinsclerosis through its function in innate immunity and via IL-13,Proc. Natl. Acad. Sci. U. S. A., 2007, 104, 2827-2830
• [30] Fichtner-Feigl S., Strober W., Kawakami K., Puri R.K., Kitani A.,IL-13 signaling through the IL-13alpha2 receptor is involvedin induction of TGF-beta1 production and fibrosis, Nat. Med.,2006, 12, 99-106
• [31] Grassegger A., Schuler G., Hessenberger G., Walder-HantichB., Jabkowski J., MacHeiner W., et al., Interferon-gamma inthe treatment of systemic sclerosis: A randomized controlledmulticentre trial, Br. J. Dermatol., 1998, 139, 639-648
• [32] Committee for medicinal products for human use assessmentreport - esbriet, http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002154/WC500103073.pdf, 2010, accessed in March1st 2015
• [33] Alleva D.G., Johnson E.B., Lio F.M., Boehme S.A., Conlon P.J.,Crowe P.D., Regulation of murine macrophage proinflammatoryand anti-inflammatory cytokines by ligands for peroxisomeproliferator-activated receptor-gamma: Counter-regulatoryactivity by IFN-gamma, J. Leukoc. Biol., 2002, 71, 677-685
• [34] Chawla A., Barak Y., Nagy L., Liao D., Tontonoz P., EvansR.M., PPAR-gamma dependent and independent effectson macrophage-gene expression in lipid metabolism andinflammation, Nat. Med., 2001, 7, 48-52
• [35] Lawrence T., Natoli G., Transcriptional regulation ofmacrophage polarization: Enabling diversity with identity, Nat.Rev. Immunol., 2011, 11, 750-761[WoS][Crossref]
• [36] Pourcet B., Pineda-Torra I., Transcriptional regulation ofmacrophage arginase 1 expression and its role in atherosclerosis,Trends Cardiovasc. Med., 2013, 23, 143-152[WoS]
• [37] Munder M., Arginase: An emerging key player in themammalian immune system, Br. J. Pharmacol., 2009, 158,638-651
• [38] Wynn T.A., Cellular and molecular mechanisms of fibrosis, J.Pathol., 2008, 214, 199-210
• [39] Trojanowska M., Role of PDGF in fibrotic diseases and systemicsclerosis, Rheumatology (Oxford), 2008, 47 Suppl 5, v2-4[Crossref]
• [40] Diep Q.N., Benkirane K., Amiri F., Cohn J.S., Endemann D.,Schiffrin E.L., PPAR alpha activator fenofibrate inhibitsmyocardial inflammation and fibrosis in angiotensin II-infusedrats, J. Mol. Cell. Cardiol., 2004, 36, 295-304[Crossref]
• [41] Jun M., Foote C., Lv J., Neal B., Patel A., Nicholls S.J., et al.,Effects of fibrates on cardiovascular outcomes: A systematicreview and meta-analysis, Lancet, 2010, 375, 1875-1884 [WoS]

Identifiers

DOI

10.1515/immun-2015-0001