Review Article PPAR-γ, Microglial Cells, and Ocular Inflammation: New Venues for Potential ...

13 Pages·2014·1.25 MB·English

HindawiPublishingCorporation
PPARResearch
Volume2008,ArticleID295784,12pages
doi:10.1155/2008/295784
Review Article
γ
PPAR- , Microglial Cells, and Ocular Inflammation:
New Venues for Potential Therapeutic Approaches
FiorellaMalchiodi-Albedi,1AndreaMatteucci,2AntoniettaBernardo,1andLuisaMinghetti1
1DepartmentofCellBiologyandNeurosciences,IstitutoSuperiorediSanita`,00161Rome,Italy
2G.B.BiettiFoundationforOphthalmology(IRCCS),00198Rome,Italy
CorrespondenceshouldbeaddressedtoLuisaMinghetti,[email protected]
Received9December2007;Accepted25January2008
RecommendedbySuofuQin
Thelastdecadehaswitnessedanincreasinginterestfortheroleplayedbytheperoxisomeproliferator-activatedreceptor-γ(PPAR-
γ)incontrollinginflammationinperipheralorgansaswellasinthebrain.ActivationofPPAR-γhasbeenshowntocontrolthe
responseofmicroglialcells,themainmacrophagepopulationfoundinbrainparenchyma,andlimittheinflammation.Theanti-
inflammatory capacity of PPAR-γ agonists has led to the hypothesis that PPAR-γ might be targeted to modulate degenerative
braindiseasesinwhichinflammationhasbeenincreasinglyrecognizedasasignificantcomponent.Recentexperimentalevidence
suggeststhatPPAR-γagonistscouldbeexploitedtotreatoculardiseasessuchasdiabeticretinopathy,age-relatedmaculardegener-
ation,autoimmuneuveitis,andopticneuritiswhereinflammationhasrelevantrole.AdditionalPPAR-γagonistbeneficialeffects
couldinvolveameliorationofretinalmicrocirculationandinhibitionofneovascularization.However,PPAR-γactivationcould,in
someinstances,aggravatetheocularpathology,forexample,byincreasingthesynthesisofvascularendothelialgrowthfactor,a
proangiogenicfactorthatcouldtriggeraviciouscircleandfurtherdeteriorateretinalperfusion.Thedevelopmentofnewinvivo
andinvitromodelstostudyocularinflammationandhowtomodulatefortheeyebenefitwillbeinstrumentalforthesearchof
effectivetherapies.
Copyright©2008FiorellaMalchiodi-Albedietal. This is an open access article distributed under the Creative Commons
AttributionLicense,whichpermitsunrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalworkis
properlycited.
1. INTRODUCTION glucoseloweringactivityofPPAR-γhasleadtothedevelop-
mentofspecificPPAR-γagonistsforthetreatmentoftype-2
The peroxisome proliferator-activated receptor-γ (PPAR-γ) diabetes and the metabolic syndrome [5]. PPAR-γ agonists
is a ligand-inducible transcription factor that belongs to such as thiazolidinediones (TZD), including pioglitazone
a large superfamily comprising the nuclear receptors for (Actos) and rosiglitazone (Avandia), increase insulin sensi-
steroids,thyroidhormones,andretinoids.ThePPAR-γ and tivitytherebyimprovingglycaemiccontrol,butalsomodify
thetwocloselyrelatedPPAR-αandPPAR-δ(alsoknownasβ, lipidemicprofileanddecreasebloodpressure[6–9].Onthe
NUC-1,orFAAR)areactivatedbynaturallyoccurringfatty other hand, fibrates, which are PPAR-α agonists, are preva-
acidsandactassensorsthatregulatewholebodymetabolism lentlyantilipidemicdrugs,andtherapeuticbenefitsofPPAR-
inresponsetothedietaryintakebycontrollinglipidandcar- α and PPAR-γ activations, which only are minimally over-
bohydratemetabolismandlipidstorage[1].AllthreePPARs, lapping, have generated interest in dual agonists that target
once agonist-activated,form heterodimers with retinoic X bothreceptors,thusofferingimprovedinsulinsensitivityand
receptors and regulate specific target gene transcription by lipidemiccontrolinthesamemolecule[10,11].Thiswould
bindingtospecificDNAregions(peroxisomeproliferatorre- provideatherapeutictoolagainstdiabetesandthemetabolic
sponseelements,PPREs)orbyamechanismindependentof syndrome.
PPRE binding, termed transrepression, which begins to be The three PPARs share a high homology, but differ for
unravelled[2]. tissue distribution and ligand specificity. PPAR-α is mainly
Becauseoftheirroleintheregulationofgenesinvolved expressed in tissues with high catabolic rates of fatty acids,
in lipid and carbohydrate metabolism, PPARs deeply affect suchastheliver,muscle,andheart,whereasPPAR-δ shows
lipid homeostasis and insulin sensitivity [3, 4]. The serum a much wider distribution. PPAR-γ is highly expressed in
2 PPARResearch
adipose tissue, where it plays a central role in the regula- drocytes,theretina-specificMuller-glialcells,andmicroglia,
tionofadipocytedifferentiation[12],andincellsoftheim- whichareconsideredthemainimmuneresidentcells.
mune system, including lymphocytes and macrophages. In Retinalmicroglia,liketheircounterpartinthebrain,be-
peripheralmonocytes,PPAR-γexpressionisinducedduring longtothemyeloidlineageandtheirmyeloidprogenitorsen-
theprocessofextravasationfrombloodvesselsintothetis- terthenervoussystemprimarilyduringembryonicandfetal
sues, and in the course of activation by pro-inflammatory periods of development. During embryogenesis, microglial
stimuli,suggestingthatPPAR-γ isimportantforpromoting precursorsmigratetotheretinabeforeretinalvascularization
monocyte-macrophage differentiation and activation and, and differentiate into ramified, quiescent microglia typical
thus,controllinginflammation[13–16].Asformacrophages of adult healthyretina. A second population of phagocytes,
ofperipheraltissues,PPAR-γregulatestheactivationofmi- whichexpressmacrophagemarkers,invadestheretinallater
croglial cells, the main macrophage population found in through the developing vasculature and remains associated
brain parenchyma, and increasing evidence indicates that with the blood vessels (see below). In the adult retina, mi-
PPAR-γ might modulate brain inflammation and neurode- crogliaaredistributedthroughmostoftheretinallayers,in-
generation[17]andbeexploitedasvaluabletherapeutictar- cludingouterplexiformlayer,outernuclearlayer,innerplex-
getinneurologicaldiseases[18].Indeed,braininflammation iformlayer,ganglioncelllayer,andnervefiberlayer.Engraft-
isincreasinglyviewedasatargetfortreatingneurologicaldis- mentexperimentshaveshownthattheydisplaysomeprolif-
eases, not only in classical infectious and immune-mediate erativecapacityandhaveaslowturnoverinrespectofother
disorderssuchasmeningitisormultiplesclerosis,butalsoin macrophage populations [21]. Disturbances in the number
stroke,trauma,andneurodegenerativediseasesthatwerenot ordistributionofthesecellsdisruptthenormaldevelopment
originallyconsideredtobeinflammatory[19,20]. oftheeyeanditsrelatedstructures.Ritterandcollaborators
In a similar way, inflammation could represent an im- [22]haverecentlyreportedthatmyeloidprogenitorsmigrate
portant target to treat ocular diseases. In the study of oph- tovascularregionsoftheretinawheretheydifferentiateinto
thalmology,theclassicalsubdivisionofpathologytextbooks microgliaandfacilitatethenormalizationofthevasculature,
in metabolic, inflammatory, hemodynamic, and degenera- thusunderliningamainroleofmicroglialcellsinpromoting
tivedisordersappearsartificialanddoesnotreflectthecom- andmaintainingretinalvasculatureduringdevelopment.
plexityofconditions,whereinflammation,dysmetabolicand Microglia show particular capacity of interaction with
hemodynamicdisorders,andneurodegenerationoftencon- retinal cells, supervising the immune environment (see
spiretothedevelopmentofdiseases.Paradigmaticexample [23] and references therein). As for microglia in the brain
isdiabeticretinopathy(DR),whereametabolicderangement parenchyma, retinal microglial cells are immunocompetent
(hyperglycemia)triggersapathologicpathway,characterized cells,abletoremovethedebriscreatedduringnormaleyede-
initiallybyinflammation(leukostasis,enhancedretinalvas- velopmentordegenerativeconditionsbyphagocytosisandto
cular permeability, Muller cell, and microglial activation), mountaninflammatoryandimmuneresponseagainstocu-
followedbymicrovasculaturealterationsandischemia(pro- larinjury,infection,anddisease.
liferative DR), eventually leading to degeneration of neu- Under normal conditions, microglia are characterized
ralretinaandvisualloss.Tothiscomplexity,asimplicityin by a downregulated phenotype when compared to other
the natural history may correspond and the course of dif- macrophage populations of peripheral tissues. The mainte-
ferent retinal diseases may at a certain stage converge to- nanceofmicrogliainthis“inhibited”stateiscrucialforthe
ward a similar evolution. For example, pathologic neovas- regulation of the immune state of the retina, which has to
cularizationmaybethesameandominousoutcomeofDR, maintaintissuehomeostasiswhilepreventingthedestructive
age-relatedmaculardegeneration(AMD),andautoimmune potentialofinflammatoryandimmuneresponse.Thecom-
uveitis,conditionsthatareveryfarfromeachotherfromthe plexityoftheseveralintraocularstructuresonwhichthecor-
pointofviewofetiology. rectvisionisdependentrenderstheeyeparticularlyvulner-
In the present article, we will first briefly review the able to the reactions of the immune system against invad-
immune cells that participate to the ocular inflammation, ing pathogens or ocular injury. To prevent that a defensive
mainlymicroglia,andtheroleofPPAR-γincontrollingtheir reaction can transform into a threat to vision in itself, the
functions.Inasecondpart,wewillconsiderthreeconditions, eye is equipped with several regulatory mechanisms, which
whereinflammationhasarelevantfunction,microgliaisin- contributetomaketheeyean“immune-privileged”site[24].
volved,andtheroleofPPARshasbeentakenintoconsidera- Asrecentlydescribedforthebrainparenchyma[25],theim-
tion:DR,AMD,andopticneuritis(ON). muneprivilegeisnotanabsoluteoranimmutablestate,but
ratheritistheresultoftheactiveinterplayamongspecialized
2. MICROGLIALCELLSANDOTHERCELL cellular elements and specific microenvironment character-
POPULATIONSOFTHEIMMUNERESPOSE istics, and it can be overcome in several instances. Among
INTHEEYE. themainfeaturesthataccountfortheocularimmuneprivi-
legeare is the presence of blood-ocular barriers (the blood-
Glial cells are the primary participants in the formation of aqueous barrier and the blood-retinal barrier), which are
scarsinresponsetoretinalorocularinjuryanddiseases.In physical barriers between the local blood vessels and most
addition, under normal conditions, they carry out a vari- partsoftheeyeitself,andthepeculiarcharacteristicsofthe
etyofsupportivefunctionsfortheneuronswithwhichthey resident immune cells, namely, microglia, which are largely
are closely related. Glial cells include astrocytes, oligoden- dependentonthepresenceofimmunomodulatoryfactors
FiorellaMalchiodi-Albedietal. 3
Table1:Retinalpathologiescharacterizedbymicroglialactivation. lieved to be essential as structural support in microcircula-
tion. In addition, together with astrocytes and Muller glia,
Pathology References
they are considered to play a major role in maintaining the
Diabeticretinopathy [26–29] innerblood-retinalbarrier[49].Thesecells,ofmesodermal
Glaucomatousopticnervedegeneration [30–33] origin,areenclosedwithinthebasallaminaontheablumi-
Humanretinitispigmentosa [34] nal surface of endothelial cells and contain contractile pro-
Age-relatedmaculardegeneration [34,35] teins. Pericytes have been shown to control vessel constric-
Retinalischemiaandreperfusioninjury [36,37] tion and retinal blood flow [50], and are involved in sev-
eral pathological conditions, including hypoxia, hyperten-
Retinaldegeneration [14,20,38]
sion,andDR.Theiractivation,sincetheveryearlyphasesof
disease,isthoughtcontributetothedisruptionoftheblood-
retinal barrier [51]. Finally, the RPE cells are important in
in the aqueous humor and on the cross-talk between mi- ocularimmuneresponseandinmaintainingtheeyeimmune
croglia and retinal cells. Several “ligand-receptor-” type in- privilege. These cells form a monolayer between the neu-
teractions between retinal cells and microglia contribute to roretinaandthechoroidsandaretheessentialcomponentof
maintainingmicrogliainanonactivatedstate.Amongthese, theouterblood-retinalbarrier.Oneofthemaincharacteris-
theglycoproteinCD200,whichintheretinaisextensivelyex- ticsofRPEcellsisthepresenceoftightjunctionsattheapical
pressedinneuronsandendothelialcells,andthecognatelig- sideoftheirlateralmembrane,whichrenderthemonolayer
andCD200Lonmicroglia[39],andtheneuronalchemokine impermeable for macromolecules and limit access of blood
fractalkine(orCX3CL1)anditsmicroglialreceptorCX3CR1 components to the retina. In addition to several important
[40]. supportive functions, including regulation of transport of
In spite of their apparent “dormant” state, resting mi- nutrientstothephotoreceptors,phagocytosisofdamagedor
crogliaactivelymonitorthesurroundingmicroenvironment old rod outer segments, and production of growth factors,
withextremelymotileprocessesandprotrusions,enteringin RPE cells contribute to the immune and inflammatory re-
contactwithothercellularelementsandsensingalterations sponse of the retina by expressing major histocompatibility
inthenearbyenvironment,towhichtheyrapidlyreact.Mi- complex(MHC)antigens,adhesionmolecules,andavariety
croglial activation comprises morphological changes, such ofcytokines,whichmayeitherpromoteorenhanceimmune
ascellularhypertrophy,retractionofprocesses,andexpres- responsesordown-regulatethem[52].
sionofsurfacemarkers,aswellasfunctionalchanges,includ- Inadditiontothecelltypessofardescribed,anovelpop-
ingproliferation,migration,phagocytosis,andproductionof ulationofdendriticcellshasbeenrecentlyreportedinnor-
bioactivemolecules.Activatedmicrogliahavebeendescribed malmouseretina,distinguishablebythecelltypesbytheex-
in several forms of retinal injury or disease (see Table 1), tent of specific surface antigens and anatomical tissue loca-
in which they are believed to play major roles, either pro- tion[53].
tective or detrimental. Indeed, activated microglia can, on
one side, remove the degenerating neurons and contribute 3. DIABETICRETINOPATHY
to re-establish tissue integrity; on the other side, they can
secreteproinflammatorycytokinessuchinterleukin(IL)-1β, Diabeticretinopathy(DR)isoneofthemostseriouscompli-
IL-3, IL-6, tumour necrosis factor (TNF)-α, and interferon cationsofdiabetesandtheleadingcauseofblindnessamong
(IFN)-γ,whichcanbetoxictoneuronsandphotoreceptors working-ageadults.DRsymptomsaremostlyduetothevas-
[41, 42] or to other cellular targets such as oligodendro- cularalterationsthataffecttheretina.Theearlyeventsarein-
cytes[43,44].Inaddition,severalofthesemicroglialprod- creasedbloodflowandabnormalvesselpermeability,dueto
uctscanup-regulatetheexpressionofvascularcelladhesion theimpairmentofblood-retinalbarrier.Theyarecausedby
moleculesandchemokines[45–47],thuspromotingthere- hyperglycemiaandtheothermetabolicconsequencesofex-
cruitmentoflymphocytesandmacrophages,andenhancing cessglucosedisposal.Asthediseaseprogresses,retinalvascu-
the immune-mediated tissue damage [23, 48]. In this con- lopathy develops, showing loss of pericytes, smooth muscle
text,moleculesthatcanenablethecontrolofmicroglialacti- and endothelial cell death, and microaneurysm formation,
vationrepresentvaluabletoolstocounteractthedetrimental resultinginareasofischemiaintheretina.Atthisstage,up-
effectsof inflammation and immune response while foster- regulationofproangiogenicfactorsinischemicretina,such
ingthosenecessaryforhealing. asvascularendothelialgrowthfactor(VEGF),initiatesavi-
Inadditiontomicroglia,othercelltypescontributetothe ciouscircleofneovascularization(proliferativeDR),charac-
immuneresponseintheeye.Theperivascularmacrophages terizedbyenhancedvascularleakageandformationofnew,
resideoutsidetheblood-ocularbarrier,inthespacethatsep- weak,andprone-to-breakbloodvessels,whichfurtherdete-
arates the endothelium of the retinal capillaries and reti- riorates retinal perfusion, worsens ischemia and eventually
nal pigment epithelium (RPE). Because of their anatom- leadstovisualloss.
ical location, they escape the tight control to which reti- Although the pathogenetic cascade connecting these
nal microglia are subjected and their morphology and im- events is still unclear, evidence suggesting a role for in-
munophenotype are very similar to those of macrophages flammationinDRisaccumulating,supportingtheinvolve-
of peripheral tissues. In close proximity, but separate from ment of both chemical mediators and inflammatory cells
perivascular macrophages are the pericytes, which are be- in the pathogenesis of the disease [54]. Elevated levels of
4 PPARResearch
proinflammatory cytokines, such as IL-1β, IL-6 and IL-8, ular hemodynamics [77]. In bovine aortic endothelial cells,
andTNF-αandvascularcelladhesionmolecule-1,havebeen troglitazone increased NO production in a dose- and time-
foundinthevitreousofpatientswithproliferativeDR[55– dependent manner with no modifications in eNOS expres-
57]. Increased VEGF and IL-6 levels were detected in the sion [78]. A study focused on NO production in pericytes
aqueous humor of diabetic patients with macular edema showedthatPPAR-γisconstitutivelyexpressedinretinalper-
[58].TNF-αwasfoundinepiretinalmembranesofprolifera- icytes and that troglitazone increases NO production and
tiveDR[59].Datafromexperimentalmodelsareinlinewith iNOS expression in a PPAR-γ-dependent manner, an effect
theseobservations.Instreptozotocin(STZ)-induceddiabetic which is opposite to what observed in cultured microglia
rats,changesinretinalbloodvesselpermeability,whichchar- [79, 80]. This study suggests that PPAR-γ agonists, in ad-
acterizes the early phases of DR, are paralleled by increase dition to improving insulin sensitivity, might also improve
in the level of the intercellular cell adhesion molecule-1 retinal microcirculation in early DR [81]. However, NO is
(ICAM-1),whichfacilitatesthetraffickingofleukocytes[60], a double-edged sword. Overproduction of NO by neuronal
andpro-inflammatorymediators,suchasTNF-αandcyclo- NOSissupposedtocontributetoretinalinjuryinischemia
oxygenase-2(COX-2)[61,62].Inthesameanimalmodel,an [82,83].Thus,althoughinDRearlyphaseanincreaseinNO
increasedlevelofIL-1βhasbeenobservedandputinrelation may contribute to the improvement of retinal microcircu-
toupregulatedinduciblenitricoxidesynthase(iNOS)[63]. lation, in proliferative DR a beneficial effect is doubtful. A
Mice deficient in the leukocyte adhesion molecules CD18 further reason of concern is represented by TZD effects on
andICAM-1demonstratesignificantlyfeweradherentleuko- VEGF.Severalinvivoandinvitrostudieshavereportedin-
cytes in the retinal vasculature after induction of diabetes creasedexpressionofVEGFinresponsetoPPAR-γ ligands.
with STZ [54]. According to some authors, VEGF could be TZDshavebeenfoundtoupregulateVEGFinhumanvascu-
responsiblefortheinitiationoftheinflammatorycascade,as larmusclecells[84],in3T3-L1adipocytes[85],incultured
itsadministrationinvivowasfoundtoinduceretinalICAM- cardiacmyofibroblasts[86].Inbovineaorticendothelialcells
1 and endothelial NOS (eNOS) expression [64, 65]. As far treatedwithtroglitazone,NOincreasewasaccompaniedby
as inflammatory cells are concerned, microglia seem to be upregulationofVEGFanditsreceptor,KDR/Flk-1[78].Ad-
mostly involved. Microglial activation appears early in the ministrationofpioglitazone[87]andtroglitazone[85]also
course of DR, before the onset of overt neuronal cell death significantly increased plasma VEGF levels in diabetic pa-
[62]. In STZ-induced diabetic rats, hypertrophic microglia tients.ConsideringtheroleplayedbyVEGFinthedevelop-
were observed one month after the onset of diabetes [66], mentandprogressionofDR,cautionhasbeensuggestedin
with significant increase also in cell number [67]. In mice theuseofPPAR-γligandsinpatientswithadvanceddisease
with alloxan-induced diabetes, changes in microglial cell [85, 87]. However, in partial disagreement with the results
morphologywerethefirstdetectablecellularmodifications, abovereported,antiangiogenicpropertiesofPPARagonists
apparentlyprecedingganglioncellapoptosisandincreasein havebeenshownbothininvitroandinvivomodels[35,88–
bloodbarrierpermeability[68].TreatmentofSTZ-induced 90].Inneonatalmice,whereischemiawasusedasamodelof
diabetic rats with minocycline, a semisynthetic tetracycline retinalneovascularization,intravitreousinjectionofrosigli-
thatcounteractsmicroglialactivation,besidesdecreasingthe tazoneortroglitazoneinhibiteddevelopmentofnewretinal
expressionofproinflammatorycytokines,decreasedcaspase- vessels [91]. In the same study, TZDs have been found to
3 levels [62], suggesting a potential neuroprotective anti- inhibit retinal endothelial cell proliferation, migration, and
apoptoticeffectofinhibitionofmicroglialactivation. tubeformationinresponsetoVEGFtreatment[91].Further
Considering the role of inflammation in the pathogen- studiesarethereforerequiredtoclarifytheissue.
esis of DR, it has been suggested that PPAR-γ ligands ex-
ert therapeutic effects also as modulators of inflammation, 4. AGE-RELATEDMACULARDEGENERATION
besides providing glycemic control [69]. In diabetic pa-
tients, PPAR-γ agonists reduce several markers of inflam- Age-related macular degeneration (AMD) is the leading
mation, such as serum levels of C-reactive protein, IL-6, cause of vision loss in the elderly in the western world. It
monocyte chemoattractant protein-1 (MCP-1), plasmino- is characterized by degeneration of the macula, the central
gen activator inhibitor-1, soluble CD40 ligand, and matrix areaoftheretinawiththehighestconcentrationofconepho-
metalloproteinase-9 [70–75]. In addition, they have been toreceptors, responsible for visual acuity and color vision.
showntoinducethesuppressionofactivatedNFκBandde- Histopathologically,theearlyphaseofAMDischaracterized
creaseROSgenerationinbloodmononuclearcells[70,73]. by formation of drusen, deposits of lipid and cellular de-
Modulation of the inflammatory process has also been bristhatarefoundbetweentheRPEcellsandBruch’smem-
studiedinDRininvivomodels.Instreptozotocin-induced brane,possiblyasaresultofRPEdegenerationor,asrecently
DR,rosiglitazonewasshowntoinhibitbothretinalleukosta- proposed[92],microglialinfiltrationandtransformationin
sisandretinalleakage[76].Theeffectwasnotaccompanied foamcells.Asthediseaseproceeds,photoreceptordegener-
by downregulation of proinflammatory cytokines, such as ationand,inthemostaggressivecases,choroidalneovascu-
TNF-α, although the adhesion molecule ICAM was found larization(CNV)intervene,withgrowthofnewbloodvessels
reduced. Nitric Oxide (NO) of endothelial origin regulates fromthechoroidsintothesubretinalspace.Twomajorclin-
ocular blood flow. In the endothelial dysfunction, which icalphenotypesofAMDarerecognized:nonexudative(dry
characterizes the early stages of DR, a reduction in the type), and exudative (wet type). The latter more frequently
bioavailability of NO may contribute to impairment of oc- developsintoCNV.
FiorellaMalchiodi-Albedietal. 5
AMD is a complex, multifactorial disease and both ge- whiledirectinjectionofmacrophagessignificantlyinhibited
netic and environmental factors may contribute at some CNV.
level.Inthepathogenesisofthedisease,bothalteredangio- As mentioned earlier, beside mononuclear phagocytic
genesis and inflammation play a role. The study of patho- cells,RPEcellshavealsoaroleintheinflammatoryandan-
logicangiogenesisintheretinahasfocusedontwomainfac- giogeneticprocess,asamajorsourceofVEGFandPEDF.In
tors: the angiogenic VEGF [93, 94] and the antiangiogenic addition,thereisacross-talkbetweenRPEandmacrophages.
PEDF [94–96], although a number of other factors are im- It has been shown that macrophages in CNV are im-
plicated(for a review, see [97]). It is widely agreed that in munopositive for VEGF, TNF-α, and IL-1β [119]. The lat-
CNVanimbalancebetweenangiogenicandanti-angiogenic ter factors can induce the secretion of IL-8 and MCP-1 in
factors takes place, but what disrupts this delicate equilib- RPEcellsinvitro[120,121].MCP-1is,inturn,involvedin
riumisstillunclear.Severallinesofevidencepointtoinflam- therecruitmentofmacrophages[122],thusclosingthecir-
mationasapathogeneticmechanism.Manyriskfactorsfor cle. Indeed, in surgically excised CNV specimens, RPE was
AMD are related to inflammation, including environmen- found to express VEGF and MCP-1 and macrophages were
talfactors,suchassmokingandlowintakeofomega-3fatty immunolabeledforVEGF[123].
acid[98,99],andgeneticfactors,suchaspolymorphismsof The interest in the role of PPARs in AMD has been
complementfactorH[100–102]andthechemokinereceptor mainly focused on their activities as modulators of angio-
CX3CR, which is expressed by microglia and mediates mi- genesis.PPARagonistshaveshownantiangiogenicproperties
grationandadhesioninresponsetoitsligandfractalkineor bothininvitroandinvivomodels[35,88,89].Ithasbeen
CX3CL1[103].IncreasedserumlevelsofIL-6andC-reactive shownthatchoroidalECsandRPEcellsexpressPPAR-γand
protein have been found to be related with progression of thatPPAR-γligandsinhibittheirresponsetoVEGF,without
AMD[104].Morerecently,IL-6receptorneutralizationhas apparent toxicity to the adjacent retina, in a laser-induced
shown to lead to decrease in the expression of inflamma- model of CNV [90]. Decrease in angiogenesis apparently
torymediators,suchasthechemokineMCP-1,theadhesion takes place by inhibition of VEGF, since PPAR-α agonists
moleculeICAM-1,andVEGF,andtoreducemacrophagein- are found to inhibit endothelial VEGFR2 expression [124].
filtration into CNV in in vivo model of the disease [105]. An opposite role has been recently described for PPARδ,
Inflammatorymediators,suchasmacrophagechemoattrac- whichinducedendothelialproliferationandangiogenesisin
tantsandactivatedcomplementcomponents,especiallyC3a vitro, through a VEGF-dependent mechanism [125]. The
and C5a, are also found in drusen samples from AMD pa- natural ligand 15-deoxy-Δ12,14-prostaglandin J (15d-PGJ )
2 2
tients[106–108].Aroleforcomplementinthedevelopment was found to protect a human RPE cell line from oxidative
of thediseasehasbeensuggested[34].Inline withthishy- stressbyelevatingGSHandenhancingMAPKactivation,but
pothesis,ithasbeenobservedthatgeneticablationofrecep- suchactivitywasindependentofitsPPAR-γbindingactivity
torsforC3aorC5areducedVEGFexpression,leukocytere- [126].Therolesofinfiltratingmacrophagesand/orresident
cruitment,andCNV[109]. microglia in the pathogenesis of AMD open the possibility
Activation of microglia and infiltration of macrophages that PPAR-γ agonists may ameliorate the course of the dis-
have been reported in the human AMD as well as in easealsothroughthedown-regulationofseveralproinflam-
experimental CNV [110–112]. In transgenic mice lack- matoryfunctionsofthesecells[8]andreferencetherein,in-
ing CX3CR1, microglia migrate defectively and accumu- cludingTNF-αandiNOS,andMHC-IIexpression.
late in the subretinal space, evoking morphological and However, possible beneficial effects of PPAR-γ agonists
pathological features similar to those observed in human in the treatment of ocular inflammation and, particularly,
AMD. In addition, laser-induced CNV was exacerbated in ofAMDneedtobefurtherverified.Itisimportanttokeep
these mice [92]. A controversy exists regarding the ori- in mind that PPAR-γ is involved in the differentiation of
gin of activated retinal mononuclear phagocytes, that is, macrophagestofoamingcellsandPPAR-γligandscaninduce
whether they are resident microglia [113, 114] or blood- expression of adipocyte lipid binding protein (ALBP/aP2),
derived bone marrow macrophages [46, 115]. In support agenethatishighlyexpressedinvivoinmacrophage/foam
of the latter hypothesis, it should be noted that systemic cellsof human atheroscleroticplaques[127].Moreover,ac-
depletionofmacrophagesusingclodronate-filledliposomes tivationofPPAR-γhasbeenshowntoreduceCCR2expres-
blocked neovascularization [116, 117]. However, the role sioninmonocytesandtheirchemotaxisinresponsetoMCP-
of macrophages is still debated, since some studies suggest 1 [128]. These PPAR-γ mediated activities are of particular
an antiangiogenic role for macrophages. For example, mice interestintheviewoftherecentfindingbyCombadie`reetal.
lackingCCchemokineligand2(CCL2)oritsreceptor,both [92], suggesting that subretinal microglial foam cells might
involved in chemoattraction of macrophages and/or mi- betheoriginofdrusen-likedepositsandthataccumulation
croglia,showdrusen-likedepositsandCNV,suggestingthat ofmicrogliainthesubretinalspacemaybeadrivingforcein
macrophage recruitment may protect against AMD [118]. thepathogenesisofAMD.
In addition, mice lacking IL-10, an anti-inflammatory cy-
tokine known to control macrophage/microglia functions, 5. OPTICNEURITISANDRELATEDDISORDERS
had significantly reduced neovascularization and increased
macrophage infiltrates compared to wild type, in a laser- Optic neuritis (ON), an inflammatory, demyelinating dis-
inducedmodelofCNV.Intheseexperiments,preventionof easeoftheopticnerve,maybetheinitialsymptomofmul-
macrophageentryintotheeyepromotedneovascularization tiple sclerosis (MS) or appear in the course of the disease.
6 PPARResearch
Table2:PPARagonistsandEAE.
Agonists Biologicalactivity Receptor References
Troglitazone Ameliorationofclinicalsymptoms.Reducedexpression PPAR-γ [129]
ofproinflammatorycytokines,IL1βandTNF-α
Decrease of severity and duration of clinical paralysis.
Ciglitazone,15d-PGJ2 DecreaseofCNSinflammationanddemyelination.De- PPAR-γ [130]
creaseofIL-12production
Delayintheonsetanddecreaseintheseverityofdisease.
15d-PGJ2 ReductionofConA-andMBPAc1–11-reactive,IFN-α- PPAR-γ [131]
andIL-4-secretingcells
Pioglitazone Decreased mRNA levels of iNOS and the chemokines PPAR-γ [132]
MIP1andRANTESinthecentralnervoussystem
Dose-dependent suppression of lymphocyte prolifera-
Gemfibrozilandfenofibrate tion. Promotion of IL-4 production and inhibition of PPAR-α [133]
IFN-γproduction
GW0742 Improvement of clinical recovery. Reduction of glial PPAR-δ [134]
activation
Ciglitazone,15d-PGJ Ameliorationofclinicalandpathologicalsymptoms.In- PPAR-γ [135]
2 hibitionofneuralantigen-specificTcellproliferation
Reductionofincidenceandclinicalsigns.Inhibitionof
Gemfibroil theinfiltrationofinflammatorycellsintotheCNS.Re- noPPAR-γ [136]
ducedexpressionofproinflammatorymoleculessuchas
iNOS,IL-1,IL-6,andTNF-α
Prevention of relapse episodes and reduction of mean
Pioglitazone clinicalscoresduringthetreatmentperiod.Decreaseof PPAR-γ [137]
IFN-γlevels
Inanyevent,nearlyhalfofMSpatientsdevelopONduring inflammatoryactivitiesofPPAR-γagonistsarecomplexand
the course of the disease. An idiopathic demyelinating dis- multifaceted,evidencehasbeenprovidedsuggestingadirect
orderoftheopticnervealsooccursasNeuroMyelitisOptica actionofPPAR-γagonistsonmicroglia/mononuclearphago-
(NMO)orDevic’sdisease,whichischaracterizedbytheco- cytic cells. Indeed, taking part in both innate and adaptive
existence of usually bilateral and severe optic neuritis with immuneresponses,microgliaandmononuclearphagocytes
spinal cord involvement and the presence of a highly spe- aredeeplyimplicatedinthecomplexinflammatorycascade
cific serum autoantibody marker (NMO-IgG), recognizing associated with MS. Their role has been recently and ex-
the transmembrane channel Aquaporin 4 [138, 139]. The tensively reviewed [144, 145]. The PPAR-γ natural agonist
boundariesbetweenNMOandMSare,however,ratherim- 15d-PGJ [146] and the PPAR-α agonist gemfibrozil [133]
2
precise,fromboththeclinicalandpathologicpointsofview were found to significantly reduce macrophage infiltration
and it is still a matter of controversy whetherNMO should in the lesions. A decreased number of IL-1β-positive cells
beconsideredavariantofMSoraseparateentity[139,140]. werefoundinEAEbrainofmicetreatedwithGW0742anda
Consideringtheirroleininflammation,thepossiblether- PPAR-δagonistandthisobservationwasconsideredindica-
apeutic efficacy of PPAR-γ agonists has been studied in ex- tive of a reduction of glial activation [134]. PPAR-γ inhibi-
perimental autoimmune encephalomyelitis (EAE), an ani- tionofmicroglialcellactivationisalsosupportedbyinvitro
mal model of the disease where the autoimmune reaction experiments[8,79,80,147–152].
against myelin is induced in animals by active sensitization Notwithstanding the amount of data regarding a thera-
with myelin components. Although several criticisms have peuticactivityofPPARagonistsin EAE,clinicalstudies are
been moved towards this model, EAE still provides a valu- lackingandreportontheirclinicaluseinMSorONisstill
abletoolforimprovingourunderstandingonthepathogen- anecdotical[153].Clinicaltrialsarehoweverincoursewith
esis and treatment of MS. EAE is also considered a model pioglitazoneandrosiglitazone.
relevant to the study of demyelinated diseases of the optic
nerve[141,142].Anadditionalanimalmodelisrepresented 6. CONCLUSIONS
byTcellreceptortransgenicmicespecificformyelinoligo-
dendrocyte glycoprotein (MOG). These mice develop iso- The promising results obtained in experimental models of
lated optic neuritis either spontaneously or after sensitiza- ocular diseases and the recent advancements in the knowl-
tionwithsuboptimaldosesofMOG[143].Therapeuticeffi- edge of the pathogenic mechanisms driving ocular damage
cacy of PPAR-γ ligands has been demonstrated in terms of and vision loss strongly point to PPAR-γ as a valuable tar-
suppression or amelioration of clinical symptoms and de- get to control inflammation and treat invalidating diseases
creaseofinflammatorysigns(seeTable2).Althoughtheanti- such as DR, AMD, and ON. Given the complexity of the
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