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[ V O L U M E 1 1 , N U M B E R 7 – 8 , J U L Y – A U G U S T 2 0 1 4 ] Innovations in CLINICAL NEUROSCIENCE 23

ABSTRACTReceptor tyrosine kinases (RTKs)

are essential components of signaltransduction pathways that mediatecell-to-cell communication and theirfunction as relay points for signalingpathways. They have a key role innumerous processes that controlcellular proliferation anddifferentiation, regulate cell growthand cellular metabolism, andpromote cell survival and apoptosis.Recently, the role of RTKs includingTCR, FLT-3, c-Kit, c-Fms, PDGFR,ephrin, neurotrophin receptor, andTAM receptor in autoimmunedisorder, especially rheumatoidarthritis and multiple sclerosis hasbeen suggested. In multiple sclerosispathogenesis, RTKs and theirtyrosine kinase enzymes are selectiveimportant targets for tyrosine kinaseinhibitor (TKI) agents. TKIs,compete with the ATP binding site ofthe catalytic domain of severaltyrosine kinases, and act as smallmolecules that have a favorable

safety profile in disease treatment.Up to now, the efficacy of TKIs innumerous animal models of MS hasbeen demonstrated, but applicationof these drugs in human diseasesshould be tested in future clinicaltrials.

INTRODUCTIONMultiple sclerosis (MS) is an

autoantigen-specific T lymphocytesdisease characterized by theinflammation, oligodendrocytedepletion, and destruction of themyelin sheath that surroundsneuronal axons in the centralnervous system (CNS), a mechanismthat leads to the formation of MSplaques in the brain and spinal cord.1

The sclerotic plaques are the mainpathological hallmark of the MSneurodegeneration, which areassociated with reactive astrogliosisand oligodendrocytes destructionaccompanied by loss of myelin andaxonal damage.2

In this autoimmune disorder, the

by ABBAS MIRSHAFIEY; GHASEM GHALAMFARSA; BABAK ASGHARI;and GHOLAMREZA AZIZIDr. Mirshafiey is from the Departmant of Immunology, School of Public Health, TehranUniversity of Medical Sciences, Tehran, Iran; Dr. Ghalamfarsa is from Cellular & MolecularResearch Center, Yasuj University of Medical Sciences, Yasuj, Iran; Dr. Asghari is fromAntimicrobial Resistance Research Center, Faculty of Medicine, Iran University of MedicalScience, Tehran, Iran; Dr. Azizi is from Imam Hassan Mojtaba Hospital, Alborz University ofMedical Sciences, Karaj, Iran.

Innov Clin Neurosci. 2014;11(7–8):23–36

FUNDING: There was no funding for thedevelopment and writing of this article.

FINANCIAL DISCLOSURES: None of theauthors have a conflict of interest in theconduct and reporting of this study.

ADDRESS CORRESPONDENCE TO: Gholamreza Azizi, Imam Hassan MojtabaHospital, Alborz University of MedicalSciences, Karaj, Iran; Fax: (+98 26) 45358204; E-mail: [email protected]

KEY WORDS: Receptor tyrosine kinase,tyrosine kinase inhibitor, multiple sclerosis

[ R E V I E W ]

Receptor TyrosineKinase and TyrosineKinase Inhibitors: New Hope for Success inMultiple Sclerosis Therapy

Innovations in CLINICAL NEUROSCIENCE [ V O L U M E 1 1 , N U M B E R 7 – 8 , J U L Y – A U G U S T 2 0 1 4 ]24

immune system cells play a pivotalrole in the pathogenesis of disease.Both CD4+ and CD8+ T lymphocyteshave been indicated in MS lesions,with CD4+ T cells predominating inacute lesions, whereas CD8+ T cellsare observed more often in chroniclesions.3 There are data linking CD4⁺T cells secreting IL-17, termed Thelper (Th) 17 cells, and IFN-γ-secreting Th1 cells with thepathogenesis of MS and its animalmodel, experimental autoimmuneencephalomyelitis (EAE).4 Activatedmyelin-reactive Th1/ Th17 cells arepresent in the blood andcerebrospinal fluid (CSF) of MSpatients, which promote blood-brainbarrier (BBB) disruption,demyelination, andneurodegeneration.3 Moreover, a T-cell dependent, macrophage-mediated, autoimmune attack onconstituents in the normal myelinsheath underlies the disease.5

In the brain lesions of MS patients,macrophage could contribute todemyelination directly byphagocytosis of myelin antigens.Macrophage also contributes todemyelination indirectly bystimulating immune cells infiltrationand inflammation in the CNS. Forexample, macrophages produce pro-inflammatory cytokines, includingTNF-α, and therefore are implicatedin the MS pathogenesis.7,8

Macrophage and Th1/Th17 cellsare infiltrated in the CNS andmediate inflammation, in part,through microglia activation. Therelease of mediators by activatedmicroglia, which are harmful foroligodendrocytes, proceedsdemyelination in MS.4 Astrocytes, asignificant component of the BBB,produce neurotoxins andneurotrophins and are handled asone of the immune effecter cells inthe CNS.9 Astrocytes couldpotentially promote MS pathogenesisin several ways,10 especially throughunrestrained proliferation ofastrocytes that result in astrogliosis,a scarring process in MS thatconcludes axonal regeneration andremyelination.11 Indeed, interactions

of the infiltrated immune cells alongwith activated resident cells(microglia and astrocytes) play apivotal role in neuroinflammatoryprocesses by releasing various kindsof noxious factors, such as matrixmetalloproteinases (MMPs) and pro-inflammatory cytokines.2, 12 It hasbeen demonstrated that MMPs play apivotal role in theimmunopathogenesis of MS, in partthrough the disruption of the BBBand the recruitment of inflammatorycells into the CNS. Moreover, MMPscan also enhance the cleavage ofmyelin basic protein (MBP) and thedemyelination process.

Therefore, inhibiting residentcells, macrophage, and Th1/Th17activation attenuates disease inanimal models of MS, and thisamelioration is accompanied by areduction in inflammatory mediatorsin the CNS.13, 14 On the other hand,the family of receptor tyrosinekinases (RTKs) has been implicatedin signaling of these cells anddemonstrated as important playersduring demyelination in both animalmodels of MS and in the humandisease.15 Finally, selective inhibitionof this enzyme would be a newstrategy in treatment of aninflammatory disease as MS.

RECEPTOR TYROSINE KINASESAND MS

Receptor tyrosine kinases (RTKs),a family of cell-surface receptors thattransduce signals to polypeptide andprotein hormones, cytokines, andgrowth factors, are key regulators ofcritical cellular processes. They havea key role in numerous processesthat affect cell proliferation anddifferentiation and cell migration andcell cycle control, as well as regulatecell growth and modulation ofcellular metabolism and promote cellsurvival and apoptosis.16,17 In thehuman genome, 58 RTKs have beenidentified that fall into 20 families;however, for normal CNS functionand neuroinflammatory diseaseprogression type III (PDGFR, CSFR,Kit, FLT-3 receptor family), type VI(PTK7/ CCK4), type VII

(neurotrophin receptor/ Trk family),type XI (TAM receptor family), andtype XIII (ephrin receptor family)RTKs are more important.18

In MS diseases pathogenesis,multiple signal transductionpathways have been implicated byRTKs and non-RTKs, including TCRand p38 MAPK signaling in T cell,FLT-3 in myeloid cells, c-Kitsignaling in mast cell, macrophage c-fms activation, TAM family ofreceptor tyrosine kinases inoligodendrocytes, and platelet-derived growth factor (PDGF) inastrocytes.15, 19, 20

TCR. the success of severalT‐cell‐targeted therapies in MSreinforces the importance of the roleof the T cell in MS pathogenesis.3

The T-cell immune response isstarted upon engagement of the TCRand co-receptor, CD4 or CD8. TCR/co-receptor engagement stimulatesthe activation of signaling pathwaysthat, in combination with signalsfrom co-stimulator molecules andcytokine receptors, direct theoutcome of the response. Activationof the src-family kinases Lck (LSTRAcell kinase) is central to the initiationof TCR signaling pathways.21 Lck isone of the human src families of non-transmembrane protein tyrosinekinases, which is required for ZAP70activation and T cell signaling.22 Itphosphorylates the CD3 and TCR ζ-chain, so that ZAP-70 is recruitedand activated, and finally conductsT-cell activation by starting nuclearfactor of activated T cells andnuclear factor-κB (NF-κB)dependent transcription of cytokinegenes.23 Therefore, Lck expression isrestricted to lymphoid cells, andselective inhibition of Lck isexpected to offer a new therapy forthe treatment of T cell-mediatedautoimmune disorders.22

Another signaling pathway in Tcells is MAP kinase. MAPKs (ERK,JNK, and p38 MAPK) are activatedby several cellular stresses, as well asin response to inflammatorycytokines. The ERK’s function is thecontrol of cell division, andsuppressors of these enzymes are


being explored as anticancer agents.The molecular mechanisms mediatedby p38 MAPK signaling cascade havebeen defined. Activation of p38MAPK cascade increases the releaseof inflammatory cytokines, such asIL-17 production in Th17 cells andIFN-γ by CD4+ Th1 cells and CD8+T-effectors cells. These pro-inflammatory cytokines are able toplay an adverse role in the targetorgans of several autoimmunediseases, such as MS.20,24,25

Krementsov et al26 recognized thissignaling pathway as a central playerin MS and its principal animal model,EAE. It is indicated that p38 MAPKactivation is required for thedevelopment and progression of bothchronic and relapsing-remittingforms of EAE. In addition, Noubadeet al20 demonstrated that theregulation of p38 MAPK activityspecifically in T cells is sufficient tomodulate EAE severity.

FLT-3. FMS-like tyrosine-3 (FLT-3) is expressed on hematopoietic anddendritic cells (DCs), which, uponbinding to FLT-3 ligand (FL),promoted cell proliferation,differentiation, and survival.27 Inbrain, FLT-3 is expressed on twocategories of cells that may have thecompetency to present antigen: onecategory is DCs and other categorymay be microglia. Activated microgliacan produce neurotoxic pro-inflammatory cytokines including IL-1β and TNF-α.28 Additionally, it isreported that FLT-3 inhibition inmurine microglia blocks IFN-γ-induced expression of MHC class IIand CD86, and LPS-inducedsecretion of IL-6. These findingsrevealed that FLT-3 is involved inmicroglial cells tendency to respondto environmental signals for acting asantigen presenting cells andmediating CNS inflammation.29

Recent data revealed that themononuclear phagocyte system,specifically DCs, plays multiplefundamental roles in thedevelopment of MS and EAE. In MSpatients, DCs are plentifully presentin brain lesions, and show an alteredphenotype and function. Hesske et

al. demonstrate that during EAEfunctionally distinct DCsubpopulations are present in theCNS. At peak of EAE, the majority ofDCs included of a CD11b+F4/ 80+inflammatory DC phenotype.30

Moreover, DCs pathologicallyinfluence the auto-reactive T and Bcells effector function.31

The significance of FLT-3 incontributing to EAE is revealed bydata showing that the onset of EAEis delayed in mice lacking FLT-3.32

Moreover, investigations show thatinhibition of FLT-3 signaling inducesapoptosis in both mouse and humanDCs, and thus could be a possibletarget for immune suppression.33

Whartenby et al. demonstrated thattargeted inhibition of FLT-3 with aselective FLT-3 inhibitor remarkablyimproved the course of establishedEAE, which was found to modulatethe maturation of DCs but had nodirect effect on T cells.33 It is showedthat treatment with FL is not capableof recruiting stimulatory/inflammatory DCs into the CNS,whereas production of granulocyte-macrophage colony-stimulatingfactor (GM-CSF) leading torecruitment of DCs populations. Thisis an important point indicating thatthe improvement in EAE of knockoutmice is not necessarily a result ofreceptor binding but possibly andindirect effect.30 Accordingly, thesedata suggest that FLT-3 might berecommended as therapeutic targeton microglia and DCs, in order tomitigate CNS inflammation in EAEand MS. 29, 34

c-Fms. The c-fms is a receptor forM-CSF (also known as CSF1), amajor growth factor for macrophage.c-fms is expressed at low levels onmonocytes, and its expressionsignificantly increases duringdifferentiation to macrophages. Theproliferation, differentiation, survival,and activation of macrophages areregulated by M-CSF/ c-fmsinteraction. Therefore c-fms iscrucial for the growth anddifferentiation of the monocyte-macrophage lineage. Moreover, M-CSF/c-fms signaling plays a key role

in macrophage accumulation intissues during inflammation and alsoregulates the production of cytokinesby macrophages.35 In vivo, it wasdemonstrated that mice deficient inM-CSF have fewer macrophages thanwild-type mice.36–38 Moreover, M-CSFis found in the brain whose receptoris expressed by microglia.Investigations indicate a pivotal rolefor M-CSF in brain development andnormal functioning as well as inseveral disease processes involvingneuroinflammation.39 Interestingly,this is demonstrated that M-CSF isup-regulated in various neurologicaldiseases, including MS and EAEdevelopment.40,41 There is littleevidence for the role of c-fmsspecifically in EAE/ MS as knockoutstudies have not been done. The onlystudy that directly implicates c-Fmsin EAE using the c-fms inhibitor,Ki20227, by Uemura et al,41 revealedthat the Ki20227 suppresses EAE.

PDGFR. In MS pathogenesis,microglia/macrophage activation andastrocyte reactivity are importantcomponents of the lesionenvironment that can impactremyelination. Astrocyte reactivitypersists throughout demyelinationand its activity is characterized byearly proliferation depends onsignaling mediated by PDGFRs.42,43

PDGF as a potent glial cell mitogen isup-regulated in peripheral bloodleukocytes in EAE. The T, NK, NKTand monocytes/ macrophages cellsexpress PDGF. The PDGFproduction by lymphocytes may havepotential therapeutic value whenactivating or modulating T-cellresponses in demyelinatingdiseases.44

PDGF binds to and induces homo-or hetero-dimerization of PDGF-Rαor PDGF-Rβ. PDGF-Rα is a well-established marker foroligodendrocyte precursor cells(cells producing the myelinmembrane around the axons in theCNS) and treatment with PDGFpromotes oligodendrocytematuration and remyelination, whilethere may be deleterious effects ofPDGF. PDGF stimulates the


activities of MAPK in protein kinaseC independent and dependentmanners.42 The involvement ofMAPK/ ERK in P2YR-mediatedastrogliosis has been disclosed invitro. The proliferation of astrocytesinduced by traumatic injury and theirmodulation by pharmacologicalligands suggests the involvement ofthe MAPK/ ERK1/2- and PI3K/Akt-pathways in astroglial proliferation.45

Thus PDGFR signaling couldcontribute to MS pathogenesis bypromoting astrocyte proliferation andconsequently astrogliosis.46 Thetyrosine kinases MAPK/ ERK andPDGFR are thus involved in keyaspects of MS pathogenesis and mayhave potential as drug targets in thetreatment of MS.

Ephrin receptor. The ephrin andephrin-related receptors have beenimplicated in mediatingdevelopmental events, particularly inthe nervous system. The ephrin-related transmembrane tyrosinekinases constitute the largest knownfamily of receptor-like tyrosinekinases, with two identifiedsubfamilies (EphA and EphB), whichhave a role in the regulation ofneuronal development, cell migrationand angiogenesis. EphA4-/- micedisplayed an abnormal CNS vascularstructure in both the cerebral cortexand the spinal cord, withdisorganized branching and a 30-percent smaller diameter.47, 48 TheEphA4 receptor tyrosine kinase is amain regulator of axonal growth andastrocyte reactivity and is aconceivable inflammatory mediator.It is demonstrated that after spinalcord injury in wild-type mice, EphA4expression was remarkably up-regulated on activated astrocytes,which were mainly associated withblood vessels. Moreover, followinginjury in EphA4-/-, spinal cord,astrocytes were not as tightlyassociated with blood vessels as thewild-type astrocytes. In uninjuredEphA4-/- mice, the BBB was normal,but it showed a prolonged leakagefollowing spinal cord injury. Thesefindings support a role for EphA4 inCNS vascular formation and

development along with an additionalrole in BBB repair.48 In recent study,Munro et al49 demonstrated that EAEwas induced in EphA4 knockoutmice and exhibited a markedly lesssevere clinical course than wild typemice, with a lower maximum diseasescore and a slightly later onset ofclinical symptoms. Moreover, EphA4knockout mice showed a decreasedaxonal pathology. Recently, it isrevealed that blocking of EphA4 inwild type mice by administration ofsoluble EphA4 (EphA4-Fc) as adecoy receptor following EAEinduction produced a delay in onsetof symptoms. These results areconsistent with a noninflammatory,CNS specific, deleterious effect ofEphA4 during neuroinflammationthat results in axonal pathology.

Amyotrophic lateral sclerosis(ALS), which is described by theprogressive degeneration of motorneurons, is one of the most commonneuromuscular disorders, but thereis just one approved therapy,riluzole, which it delays the onset ofventilator-dependence ortracheostomy in selected patientsand may increase survival. A study inNature Medicine showed thatEphA4 can modulate motor neurondegeneration and diseaseprogression in ALS.50 In humans withALS, EphA4 expression inverselycorrelates with disease onset andsurvival, and loss-of-functionmutations in EphA4 are affiliatedwith long survival. This indicates thatEphA4 generically modulates thevulnerability of motor neurons toaxonal degeneration and may displaya new target for therapeuticintervention.51

VEGFR. The active lesions in MSare characterized by BBBbreakdown, up-regulation ofadhesion molecules on capillaryendothelial cells, and perivascularinflammation, suggesting that alteredvessel permeability and activatedendothelial cells are involved in thepathogenesis of the disease. VEGFmediates multiple aspects of bloodvessel physiology includingpermeability, regulation of growth,

and inflammation.52 To investigate apossible relationship betweenexpression of VEGF and CNSautoimmune disease, Proescholdt etal52 examined VEGF expression inMS plaques and showed VEGFexpression was consistently up-regulated in both acute and chronicMS plaques. Also during the courseof EAE, VEGF-positive cells withastrocytic morphology increased inthe spinal cord during thedevelopment of EAE and were foundthat the inflammatory cells such as Tcells, macrophages and activatedglia, are able to produce VEGF. Inaddition, intracerebral infusion ofVEGF in animals which have beenpreviously immunized with MBPinduced an inflammatory response inthe brain. These results suggest thatoverexpression of VEGF mayaggravate the inflammatory responsein CNS autoimmune diseases byinducing focal BBB breakdown andinflammatory cells migration into thelesions. Moreover, an increasedexpression of VEGF is associatedwith demyelinated lesions in both MSand EAE, implicating changes invasculature as a potential componentof CNS plaque formation.53 Seabrooket al54 demonstrated glial expressionof VEGF and glial and blood vesselexpression of the pro-angiogenicreceptor VEGFR2 on chronic activehuman MS plaque.

TAM receptor. TAM family ofRTKs (TYRO3, AXL and MERTK)plays pivotal roles in the processes ofcell survival and proliferation,modulation of the immune response,and the removal of dead cells fromtissue. Disruption of these processeshas been shown to be central to boththe initial development, and thesubsequent clinical course ofdemyelinating diseases. All threereceptors (TYRO3, AXL andMERTK) and their ligands, Gas6(growth arrest-specific gene 6) andprotein S, are expressed in myelin-producing cell, oligodendrocytes inthe CNS.55 Recent studies haveshown that Gas6-dependent TAMreceptor signaling is an importantmodulator of oligodendrocyte


survival and microglial phenotypeboth in vitro and in vivo.55

In 2009, Binder and Kilpatrick55

proposed that TAM family has beenimplicated as important playersduring demyelination in both animalmodels of MS and in the humandisease. During a demyelinatingchallenge, dysfunctional TAMreceptor signaling could lead to a'vicious cycle of cell death, reducedphagocytosis, and detrimentalimmune hyper-activation.

In the nervous system, Axl and itsligand Gas6 are expressed onmultiple cell types. Axl functions indampening the immune response,regulating cytokine secretion,clearing apoptotic cells and debrisand maintaining cell survival. Axl isup-regulated in various diseasestates, such as cuprizone toxicity-induced model of demyelination andin MS lesions, suggesting that it playsa main role in disease pathogenesis.56

Weinger et al 57, 58 showed that up-regulation of soluble Axl and MerRTKs negatively associates with Gas6in MS lesions. While in normal tissueGas6 significantly affiliated withsoluble Axl and Mer, there was anegative correlation in establishedMS lesions between Gas6 and solubleAxl and Mer. Moreover, it isdemonstrated that augmented levelsof soluble Axl and Mer werecorrelated with increased levels ofmature ADAM17 and ADAM10, aswell as furin, proteins that areconnected with solubilization of Axland Mer. Therefore, soluble Axl andMer function both as decoy receptorsare blocking of Gas6 binding tomembrane-bound receptors. Thesefindings establish Gas6 as animportant regulator of both CNSdemyelination and remyelination.Furthermore, in MS lesions,dysregulation of protective Gas6receptor signaling may prolong lesionactivity in MS lesions.

In another study, Weinger et al56

showed that Axl alleviates EAEdisease progression and suggestingthat Axl has functions in therecruitment of microglia/macrophages as well as in the

clearance of debris followingdemyelination. Accordingly, thesedata provide further support thatadministration of the Axl ligand Gas6could be a therapeutic strategy forimmune-mediated demyelinatingdiseases. In addition, Ma et al15

suggested that the MERTK gene is anovel risk gene for MS predispositionand polymorphisms in the receptortyrosine kinase MERTK gene areassociated with MS susceptibility.

Neurotrophin receptor. Theneurotrophin receptor family ofRTKs includes tyrosine kinase A, Band C (trkA, trkB and trkC)receptors, which respond to nervegrowth factor (NGF), brain-derivedneurotrophic factor (BDNF), andneurotrophin3 (NT3), respectively.They are associated primarily withproliferative and migration effects inneural systems. While matureneurotrophins exhibitneuroprotective roles via TrkA, TrkBand TrkC, the pro-forms ofneurotrophins show totally differentbiological effects that may induceapoptotic cell death of neurons bytriggering p75NTR (p75neurotrophin receptor)-sortilinsignaling cascades.59 The receptor forNGF encompasses a p75NTR and aTrkA subunit. TrkA-mediated rescuefrom apoptosis is correlated withMAPK activation. Simultaneously,activation of TrkA inoligodendrocytes resulted insuppression of c-jun kinase activityinitiated by p75. Therefore TrkA-mediated rescue involves not onlyactivation of survival signals but alsoconcurrent suppression of a deathsignal by p75.60 In an animal study,Valdo et al61 showed that at the edgeof chronic active MS lesions,selective NGFRp75 was prominenton reactive astrocytes, whilethroughout the lesion, NGFRp75 wasexpressed on microglia/ macrophagesand the vast majority of mature orprecursor oligodendrocytes did notexpress NGFRp75. Consequently,expression of NGF receptors inactive MS lesions indicates a criticalrole for NGF in regulating theautoimmune response at both

immune and glial cell levels.It is recently shown that human

immune cells are capable ofproducing the BDNF, which canprevent axonal and neuronal damageafter various pathological insults.BDNF imported into the CNS byimmune cells would thus be anattractive candidate for mediatingneuroprotective effects in MS. In MSlesions, BDNF is primarily present inimmune cells (T cells, macrophages/microglia), and reactive astrocytesand the number of BDNFimmunopositive cells correlated withlesional demyelinating activity. TheBDNF receptor gp145trkB is foundin neurons in the immediate vicinityof MS plaques as well as in reactiveastrocytes within the lesion, but notin immune cells.62 On the contraryanother findings by De Santi et al63

revealed that gp145trkB is mainlyexpressed on T cell lines from MSpatients and that the BDNF/gp145trkB axis is involved in theregulation of peripheral T-cellapoptosis in MS. These data suggestthat BDNF and its receptorgp145trkB are involved in immune-mediated neuroprotectiveinteractions in MS and support theconcept that immune cells produceboth damaging and protective factorsin MS lesions.62

c-Kit. The receptor tyrosinekinase c- Kit (also called CD117 andstem cell factor receptor) is a 145 kDtransmembrane protein, which actsas a key controller receptor for anumber of cell types, including mastcells, astrocytes, hematopoietic stemcells, and lineage progenitor cells.64,65

In most lineages, c-Kit is down-regulated during cell development,except for mast cells. In mast cells,high expression of c-kit is maintainedduring development and its signalingis essential for mast celldevelopment.64 Recent researchesdemonstrated that mast cells havehad pathogenic role in thedevelopment of autoimmunediseases, including EAE. It is shownthat mast cell-deficient c-Kit mutantKit(W/ W-v) mice are protectedagainst EAE, suggesting a


detrimental role for mast cells in thisdisease. As Piconese et al66 observed,MOG-induced chronic EAE wasexacerbated in Kit(W-sh/ W-sh)compared with Kit(+/ +) mice. Inaddition, Kit(W-sh/ W-sh) miceshowed more inflammatory foci inthe CNS and increased T-cellresponse against myelin. However, insome another research animmunoregulatory function of mastcells has recently been suggested.67

Obtained data by Li at al67 indicatethat mast cells responsiveness is notrequired in the pathogenesis ofinflammatory demyelination in theCNS and that, in the absence of mastcells, increased MCP-1, CCR2, IL-17,IFN-γ, CD44, and other inflammatorymolecules may be responsible forincreased severity of EAE.

TYROSINE KINASE INHIBITORSProtein tyrosine kinases (PTKs)

regulate proliferation, differentiation,and signaling processes in the cellsof the immune system. Uncontrolledsignaling from RTKs and intracellulartyrosine kinases can lead toinflammatory responses. RTKs aredrug targets in many types of diseasespecially cancer and autoimmunedisease. Many diseases result ingenetic changes or abnormalities thateither alters the abundance, activity,cellular distribution and regulation ofRTKs. Drugs that modify thedysregulated functions of thesereceptors fall into two categories.One group is often described as“biologicals,” which block theactivation of RTKs directly or bychelating the cognate ligands, whilethe second are small moleculesdesigned to inhibit the tyrosinekinase activity directly.68 Thus,inhibitors that block the activity oftyrosine kinases and the signalingpathways may provide a useful basisfor drug development.69 Recently, itwas demonstrated that TKIs haveimmunomodulatory effects onimmune cells implicated inautoimmune disorders.70 TKIs are aclass of chemotherapy medicationsthat block, or inhibit, the enzymetyrosine kinase. In this category,

imatinib was the first to beintroduced into clinical oncology, andit was then followed by the drugssorafenib, dasatinib, sunitinib,nilotinib, gefitinib, erlotinib,bosutinib, lapatinib, pazopanib, andregorafenib. Although they share thesame mechanism of action (it is acompetitive ATP inhibitor at thecatalytic binding site of tyrosinekinase), they differ from each otherin the spectrum of targeted kinases,pharmacokinetics, and substance-specific adverse side effects.71

Besides the hematological sideeffects of most of TKIs (e.g., anemia,neutropenia, and thrombopenia), themost common extra-hematologicadverse side effects are edema,nausea, vomiting, diarrhea, andhypothyroidism. With variations fromdrug to drug, TKIs cause skintoxicity, including folliculitis, in morethan 50 percent of patients. Amongthe TKIs that are commerciallyaccessible, the agents that targetEGFR (gefitinib and erlotinib)display the broadest spectrum of sideeffects on skin and hair, includingfolliculitis, paronychia, facialerythema, facial hair growth, andvarying forms of frontal alopecia. Incontrast, folliculitis is not commonduring administration of sorafeniband sunitinib, which target PDGFR,VEGFR, FLT-3, and others, whereasboth agents have been associatedwith subungual splinterhemorrhages. Periorbital edema is acommon side effect of imatinib.Though TKIs entirely appear to be awell tolerated drug class, cardiactoxicity with congestive heart failureis under investigation in patientsreceiving imatinib and sunitinib,though this perceived side effectmight be more related to patientselection.71

Imatinib mesylate. Imatinib(originally STI571) is a drug used totreat certain types of cancer. It iscurrently marketed by Novartis asGleevec or Glivec as its mesylate salt,imatinib mesilate. Imatinib mesylate,an orally administered 2-phenylaminopyrimidine derivative, isformulated in hard capsules or

tablets as a salt (imatinib methanesulfonate or mesylate, molecularweight: 589.7). Each tablet contains100mg or 400mg of imatinib freebase. The hard capsule is dosed at100mg of base.72 In 2011, Gleevecwas approved by the United StatesFood and Drug Administration(FDA) to treat 10 different cancers.This drug is a selective proteintyrosine kinase inhibitor, which wasexpanded to inhibit BCR- Abl kinaseactivity in CML and c-Kit express ingastrointestinal stromal tumors(GIST). In addition to BCR- Abl andc-Kit, two other tyrosine kinasereceptors inhibited by imatinib arethe c-fms and PDGFR receptors.Imatinib also blocks the activity ofthe tyrosine kinases, such as Lck,MAPK and FLT-3. 73, 74 Research hasshown that imatinib hasimmunomodulatory effects and anti-proliferative activity on various cellstypes so that imatinib can act onnormal cells of immune system andmodulate the differentiation,proliferation, activation, and functionof these cells, including Tlymphocytes, macrophage, andDC.75,76

Imatinib directly inhibits TCR/Abltyrosine kinase signaling pathwayand therefore could significantlyreduce ZAP70 and LAT tyrosinephosphorylation in response to T-cellactivation through the TCR andLCK.77 In addition, imatinib candiminish the levels of activated NF-κB and change phosphorylation orprotein levels of Lck and ERK1/2during T-cell stimulation.78 Alongwith modulatory effect of imatinib onT-cell functions and activation,imatinib decreases IL-2, IL-17, andIFN-γ production by activated T-cellsand also inhibits release of granzymeB by CD8+ T lymphocytes.79 It wasdemonstrated that imatinib inhibitsantigen-specific IFN- γ production ofboth CD4+ and CD8+ T-effector cellsat therapeutically relevantconcentrations, while T cells stayresponsive.80 Interestingly, thedecrease of IFN- γ production wasnot due to the lack of T-cell viability.Therefore, imatinib inhibits T-cell


response, but does not effect T-cellapoptosis, so long-term imatinibadministration in high doses mighthave an effect on T cells in immunesystem.81 Leder et al80 showed thatthe effector T cells are modulatedrather than suppressed because thecytolytic functions of cytotoxic Tcells were not changed. Thesefindings provide evidence for atherapeutically relevant modulationof T-cell effector functions viaimatinib. Agosti et al65, 82

demonstrated that treatment ofnormal mice with imatinib, alongwith deficit in pro T and pro B celldevelopment, also inhibitedastrocytes and mast cellproliferation. Crespo et al46 revealedthat imatinib inhibited astrocyteproliferation mediated by thePDGFR, a process involved in thetypical astrogliosis of MS. Moreover,imatinib can inhibit SCF-induced c-Kit phosphorylation and downstreamactivation of MAPK pathways in mastcell accompanied by a decreasedproduction of TNF-α, IL-6 and GM-CSF pro-inflammatory cytokines.83

Hence, the receptor tyrosine kinasesmight be considered as therapeutictargets for imatinib to alleviatecytokine-mediated disorders duringCNS inflammation in EAE and MS,and to inhibit recruitment ofinflammatory cells to the CNS byreducing the TNF-α, IL-1β, and IL-6secretion7. Recently, Moawad showedthat histologic grade and TNF-α levelin mouse model of MS would bestrongly and inversely correlated inattenuating MS effectively byimatinib therapy.84

Imatinib is able to inhibite IL-6and TNF-α secretion bymacrophages, as well as reducingdelayed hypersensitivity in mice.81 Inaddition, it has an inhibitory effecton macrophage proliferation anddevelopment induced by both M-CSFand GM-CSF through decreasing c-fms signaling and functionalactivity.85,86 In the presence oftherapeutic concentrations ofimatinib, human monocyte-derivedDCs generated a reduced expressionof MHC class I and II, CD1a, and co-

stimulatory molecules (e.g., CD40and CD80), and also decreasedsecretion of cytokines, resulting in animpaired ability of DCs to elicitprimary T-cell responses.87 Themodulatory effects of imatinib werealong with down-regulation ofnuclear localized RelB protein. Thesedata revealed that imatinib caninhibit the differentiation andfunction of DCs, which is in partmediated through the NF-κB signaltransduction pathway.75

The TKI imatinib withimmunomodulatory and anti-inflammatory properties canattenuate CIA, EAE,glomerulonephritis and autoimmunediabetes in animal models.70, 81, 88 InMS and its animal model, it isdemonstrated that imatinib can beeffective in attenuation ofinflammatory process in CNS. Crespoet al46 in 2011 showed imatinib candiminish the development of EAEand treat established disease in a ratmodel of MS. These data weresupported by Azizi et al89 thatshowed imatinib has potentialtherapeutic effects on EAE byattenuation in the severity and delayin the onset of EAE in C57BL/ 6mice. In the only clinical trial inhumans, it was founded that imatinibameliorated neurologic deficits in arare case of simultaneous associationof missed MS and chronicmyeloblastic leukemia.90 Although,very low influence into the CNS ofhumans with accurate BBB has beenreported for imatinib,91 however thesurveys about imatinibs influence onCNS cells is still controversial.Recent prosperities in animal modelstreatment to clarify the therapeuticeffect of imatinib on EAE has beenachieved with regard to the fact thatthe BBB is compromised as a resultof the disease pathology, anddissociation of the BBB allowingaccess to imatinib via serumingredients.92 In addition it issuggested that BBB is a target forimatinib, as Chi et al93 suggested thatin one side, imatinib reduces BBBdisruption and stroke volume bytargeting PDGFR-α signaling,

following an experimentally inducedischemic stroke. Here theydemonstrate that PDGFR-α signalingis a pivotal regulator of BBB integrityduring neuroinflammation.

On the other side, MMP-2 can beexpressed in CNS by resident cellssuch as reactive astrocytes andseems to play a key role in BBBdisruption which facilitates immunecell migration into the CNS.Moreover the over expression ofMMP-2 is associated withfragmentation of MBP, degrading themyelin sheath, and damagingaxons.94-96 Recently Azizi et al89

showed that imatinib inhibited MMP-2 expression and activity inglioblastoma and astrocytoma celllines. In another study Schultz et al97

showed that MMP-2 expression wassuppressed in the presence ofimatinib in HNSCC cell lines due toinhibition of receptor tyrosinekinases c-kit. Finally, Down-regulation of MMP-2 by imatinibcould inhibit BBB disruption andmigration ability of inflammatorycells to CNS, and therefore imatinibshould be discussed as a potentiallyeffective treatment for MS. Inconsistent with this data, Adzemovicet al98 revealed that imatinibaugments BBB integrity in EAE ratmodel accompanied by reduced CNSinflammation, modulating theperipheral immune response andespecially reduced T-cellrecruitment. This phenomenon wassupported by down-regulation of theCCR2 in CNS and lymph nodes, andby modulation of the peripheralimmune response towards an anti-inflammatory phenotype.Interestingly, imatinib alleviatedneuroinflammation, even when thetreatment was initiated after theclinical manifestation of the EAE.98

Sunitinib. Sunitinib (marketed asSutent by Pfizer) is an orallyavailable small-molecule multi-kinaseinhibitor. This agent potently inhibitsthe VEGFR, PDGFR, FLT-3 and c-Kitin addition to other kinases inbiochemical and cell-based assays.99

Sunitinib was approved by the FDAfor the treatment of renal cell


carcinoma and imatinib-resistantGIST. Sunitinib may be also used totreat a rare type of pancreatic cancercalled a neuroendocrine tumour.

Information regarding the directeffects of sunitinib on brain-derivedneurons is confined. In a study bySon et al100 it is revealed that theinjection of sunitinib reducespathologic autophagic vacuolesformation in the brains of the APP/PS1 double transgenic AD mousemodel. In a same study, the increasein pathologic vacuole formation inthe human neuroblastoma cell line byamyloid beta was reduced bysunitinib. On the other side, sunitinibhas been shown to arouse autophagyin the neuronal-like PC12 cell line, aneffect that is mediated by inhibitionof the mTOR signaling pathway.101

Moreover, examination of culturedneurons derived from the Tg2576mouse model of AD reveals thattreatment with Semaxanib, acompound closely related tosunitinib, does not affect cell viabilitybut does alter processing of theamyloid precursor protein.102

In a new study in 2013 Sanchez etal103 proposed that sunitinib increasesneuronal survival and thisneurotrophic effect is mediated byNF-κB. Moreover, the inflammatoryproteins COX2 and NOS2 are up-regulated by sunitinib in an NF-κB-dependent manner. These data are inagreement with a growing literaturesuggesting beneficial effects forinflammatory mediators such as NF-κB, COX2 and NOS2 in neurons.Further work is needed to fullyexplore the effects of sunitinib in thebrain and its possible use as atreatment for MS. Finally, sunitinibmay be useful for the treatment of arange of CNS diseases as MS.

Lestaurtinib (CEP-701).Lestaurtinib is a TKI of FLT-3, JAK2,and neurotrophin receptor family. Itis undergoing research for thetreatment of acute myelogenousleukemia (AML) andmyeloproliferative disorders.104, 105 Inimmune system DCs in the peripheryand microglia in the CNS couldexpress FLT-3, and are responsible

for cytokine polarization andexpansion of T cell subset. On theother side, recent data in MS fieldsuggest FLT-3 is expressed on DCsin perivascular regions of the EAEbrain, but FLT-3 is also expressed ona non-DC type such as the microgliain these regions and within the brainparenchyma.29, 106

Whartenby et al33 demonstratedthat inhibition of FLT-3 signaling bylestaurtinib would thus produce aninhibition of DC-induced stimulationof T cells, thereby inhibitingautoimmune responses. Skarica etal32 indicate that in vivoadministration of lestaurtinib thattargets DCs to mice with EAE led toa decrease in CNS infiltration ofpathogenic Ag-specific T cells. Otherresults also showed a decrease inproduction of TNF-α, IL-6, and IL-23by DCs as well as a decrease in co-stimulatory molecules expression.Moreover it is demonstrated thatlevels of phospho-Stat1, Stat3, Stat5,and NF-κB, which are signalingmolecules that have been implicatedin these pathways, were decreased.In another study, DeBoy et al29

revealed that treatment of activatedmicroglia with FLT-3 inhibitor,lestaurtinib, results in a dose-dependent decrease of surfaceexpression of MHCII and CD86 andsecretion of IL-6. These data displaythat peripheral DCs are the primarytarget but that microglia is alsomodestly affected by lestaurtinib, asnumbers and activation states of thecells in the CNS are decreased aftertherapy.32 Therefore, targetedinhibition of FLT-3 in DCs andmicroglia by lestaurtinib significantlyimproved the course of establisheddisease in EAE, suggesting apotential avenue for treating MSdisease.33

Sorafenib. Sorafenib (Nexavar)is a small molecular inhibitor ofseveral tyrosine kinases (VEGFR , cKit and PDGFR) and Raf kinases. Inaddition, sorafenib is a unique agentin targeting the MAP kinase pathway.Sorafenib is approved for thetreatment of primary kidney cancerand advanced primary liver

cancer.107,108

Massard et al109 in 2006 suggestedthat sorafenib, is probably able topenetrate the BBB. In a researchusing MS animal model, Crespo et al46

tested the therapeutic efficacy of twoTKI: sorafenib and GW2580, an orallybioavailable inhibitor of c-fms kinase.GW2580 is a relatively specificinhibitor of c-fms that can attenuateautoimmune arthritis in mice,110 andalso completely inhibited human c-fms kinase in vitro.111 Crespo et al46

showed that sorafenib and GW2580can each effectively treat EAE.Sorafenib abrogated PDGF-inducedproliferation of astrocytes, whereasboth GW2580 and sorafenibsuppressed TNF-α production bymacrophages. In another studyConway et al111 showed that GW2580inhibited LPS-induced TNF-αproduction in mice, in contrast toeffects on monocytes andmacrophages in vitro. The ability ofGW2580 to chronically inhibitedCSF-1 signaling through c-fms kinasein normal immune cells in vivo makesGW2580 a useful target in assessingthe role of c-fms kinase in normaland disease processes as MS.

Ki20227, a novel quinoline-ureaderivative is a c-fms TKI which maybe candidate as a drug for thetreatment of human MS. Ki20227 caninhibit c-fms, KDR, c-Kit, andPDGFR-β but does not inhibit otherkinases, such as FLT-3, epidermalgrowth factor receptor, or c-Src.112

Uemura et al 41 investigated whetherKi20227 has suppressive effects uponEAE and indeed found that this drugsignificantly reduced the severity ofEAE both preventively andtherapeutically. Remarkably, Ki20227treatments inhibited the turn-over/expansion of myeloid cells stimulatedby the immunization and subsequentMOG-specific T cell responses in MSanimal model.

The TKIs of VEGFRs are ATP-mimetic proteins that bind to theATP-binding catalytic site of thetyrosine kinase domain of VEGFRs,resulting in blockade of intracellularsignaling. Several of these agents asCediranib (AZD2171) and semaxinib


(SU5416) are currently in differentphases of clinical development.113, 114

Roscoe et al53, 115 investigated thefunctional contribution of VEGF inacute and chronic EAE by treatingimmunized mice with semaxinib, apotent and selective inhibitor ofVEGFR2. In an acute status,semaxinib treatment produced asignificant clinical improvementversus vehicle controls, with lessdemyelination and cellular infiltrationin the spinal cord. In addition,treated animals had significantlyfewer blood vessels than controls,and significantly reduced lamininabnormalities. There was noimprovement in clinical score ortissue pathology, and no difference invessel number, when semaxinib wasadministered during the chronicdisease.

As mentioned mast cells activelyparticipate in the pathogenesis ofMS, in part because they secretelarge amounts of various mediatorsthat sustain the inflammatorynetwork. Masitinib (AB1010), aselective oral TKI, effectively inhibitsthe survival, migration and activity ofmast cells. Vermersch et al116

demonstrated that masitinib has apositive effect on primaryprogressive MS (PPMS) or relapse-free secondary progressive MS(rfSPMS) patients, as evidenced byan improvement in MSFC scoresrelative to baseline, compared with aworsening MSFC score in patientsreceiving placebo. These datasuggest that masitinib hastherapeutic benefit to PPMS andSPMS patients and could thereforerepresent an innovative avenue oftreatment for this disease.

CONCLUSIONIn MS pathogenesis the tyrosine

kinases are involved in key aspectsand may have potential as drugtargets in the treatment of thisdisease. RTK inhibitors can exertnumerous effects on multiple celltypes, affecting immuneresponsiveness and inflammatoryprocesses. Several reports representthat these agents have direct effects

on inflammatory mediators andprocesses in the brain and peripheryimmune system.81, 98 In addition,TKIs can be administered orally tothe patients and comparativelylimited adverse effects have beenreported for theseimmunomodulatory drugs than usualdrugs used for MS treatment. Up Tonow, the efficacy of some TKIs inanimal models of MS has beendemonstrated, but application ofthese drugs in human should betested in future clinical trials.70

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[review] receptor tyrosine kinase and … tyrosine.pdf...important targets for tyrosine kinase...

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