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Review ArticleReview Article

The Purinergic System as a Pharmacological Target for the Treatment of Immune-Mediated Inflammatory Diseases

Luca Antonioli, Corrado Blandizzi, Pál Pacher and György Haskó
Clive Page, ASSOCIATE EDITOR
Pharmacological Reviews July 2019, 71 (3) 345-382; DOI: https://doi.org/10.1124/pr.117.014878

Article Figures & Data

Figures

  • Fig. 1.
    Fig. 1.

    Schematic diagram of the purinergic signaling complex. Once released into the extracellular environment, through channels or other extrusion systems, ATP exerts its extracellular effects by binding P2 receptors (P2X and P2Y). ATP is degraded by the nucleotidases CD39 and CD73, leading to the sequential dephosphorylation of ATP to ADP and AMP and subsequent generation of the bioactive metabolite adenosine, which activates P1 (A1, A2A, A2B, and A3) receptors. The CD38-CD203a (ectonucleotide pyrophosphatase/phosphodiesterase 3) enzyme axis on the cell surface, operating independently or in synergy with the conventional CD39/CD73 pathway, also contributes to the generation of the adenosine. Several cell types are endowed with nucleoside transporters (NT) and adenosine deaminase, which mediate the uptake or deamination of extracellular adenosine, respectively, thus actively participating in the termination of adenosine signaling. ADP, adenosine diphosphate; ADPR, ADP-ribose; AMP, adenosine monophosphate; ATP, adenosine triphosphate; NAD+, nicotinamide adenine dinucleotide.

  • Fig. 2.
    Fig. 2.

    Schematic representation depicting the role of the purinergic system in neuroimmunological alterations in an experimental model of experimental autoimmune myasthenia gravis. In healthy conditions, endogenous adenosine generated from the activity of CD73 counteracts the proinflammatory activity of Teff cells, by acting on A2A receptor expressed on them and by increasing the activity of Treg cells. In addition, in the motor endplate, adenosine, arising from ATP degradation, facilitates acetylcholine release via the stimulation of A2A receptors expressed at the prejunctional level. In myasthenic animals, there is reduced production of endogenous adenosine. In addition, adenosine degradation is increased, which is related with an increase in plasma adenosine deaminase activity. This results in increased production of autoAbs against nAChR and thus a loss of peripheral tolerance to nAChR. ACh, acetylcholine; ADA, adenosine deaminase; nAChr, nicotinic receptor.

  • Fig. 3.
    Fig. 3.

    Role of adenosine in modulating keratinocyte proliferation. Psoriatic patients are characterized by an abnormal hyperproliferation and differentiation of keratinocytes. In this context, endogenous adenosine participates in the hyperkeratosis process by increasing the proliferation of keratinocytes via the engagement of A2A receptors, which are overexpressed in psoriatic patients.

  • Fig. 4.
    Fig. 4.

    Schematic representation showing the involvement of adenosine metabolism in regulating the level of A2B receptor activation, in normal conditions (A) and in the presence of inflammatory bowel diseases (IBDs) (B). CD73 produces adenosine, but its levels are decreased in IBD by increased uptake into epithelial cells through upregulated NTs. The stimulation of A2B receptors participates in maintaining the integrity of epithelial barrier by sustaining the phosphorylation of VASP and thus strengthening the expression of tight junction protein, such as ZO-1, Clau, and Occl. This process is impaired during IBD. AMP, adenosine monophosphate; Clau, claudin; NT, nucleoside transporter; Occl, occluding; VASP, vasodilator-stimulated phosphoprotein; ZO-1, zonulin-1.

  • Fig. 5.
    Fig. 5.

    Scheme illustrating the overlapping cellular alterations in components of the purinergic signaling complex in immune-mediated inflammatory diseases.

Tables

  • TABLE 1

    Selective ligands for purinergic receptors

    ReceptorSignalingAgonistsAntagonistsAllosteric modulators
    P2 receptors
    P2X1ligand-gated ion channel2-MeSATP, L-β,γ-meATP, α,β-meATP, BzATP, HT-AMP, PAPET-ATP, Ap5A, CTPTNP-ATP, Ip5I, NF023, NF449, NF 279, PPNDS, Ro 0437626, IsoPPADS, MRS2159, phenol red, suramin—
    P2X2ligand-gated ion channel—NF770, NF778, NF 279, PSB-10211, PPADS, RB-2, suramin, TNP-ATP—
    P2X3ligand-gated ion channel2-MeSATP, α,β-meATP, BzATP, D-β,γ-Me-ATP, 2-MeSATP, HT-AMP, PAPET-ATP, Ap5ATNP-ATP, A317491, AF-906, AF-219, RO3, NF110, spinorphin—
    P2X4ligand-gated ion channel—BX-430, BBG, phenolphtalein, TNP-ATP 5-BDBD, PSB-12062, paroxetineIvermectin (positive)
    P2X5ligand-gated ion channel———
    P2X6ligand-gated ion channel———
    P2X7ligand-gated ion channel—Brilliant Blue G, A804598, A839977, decavanadate, KN62, KN-04, BBG, oxidized-ATP, A740003, A438079, AZ10606110AZ10606120 (negative), GW791343 (positive), GW791343 (negative), chelerythrine (negative), AZ11645373(negative) KN62 (negative) Ivermectin (positive)
    P2Y1Gq2-Cl-ADP(α-BH3), 2-MeSADP, ADPβS, MRS 2365MRS2500, MRS2279, MRS2179, PIT2,2′-pyrydilisatogen tosylate (negative), BMS compound 16 (negative)
    P2Y2GqUTPgS, Ap4A, 2-thioUTP, MRS2698, MRS2768, PSB1114——
    P2Y4GqMRS4062, MRS2927, (N)methanocarba UTP, UTPγSPPADS, reactive blue-2, ATP—
    P2Y6GqUDP, 3-phenacyl UDP PSB0474, MRS2693, MRS2957MRS2578, MRS2567—
    P2Y11GqATPγS, NF546, AR-C67085, NAD+NF157, NF340—
    P2Y12Gi2-MeSADP, ADPβSPSB-0739, AR-C 66096, ATP, AZD1283, ARL66096, cangrelor, Ap4a, ticlopidine
    P2Y13Gi2-MeSADP, 2-MeSATPMRS2211, MRS2603, cangrelor, Ap4a
    P2Y14GiMRS2905, αβ methilen 2-thioUTP, 2-thioUDPPPTN
    P1 receptors
    A1Gi/0R-PIA, GW493838, CHA, CPA, CCPA, TCPA, 2′-Me-CCPA, GR79236, selodenoson, capadenoson, tecadenoson, GS9667PSB36, DPCPX, CPFPX, KW-3902, toponafylline derenofylline, FK-453, SLV320, WRC-0571, DU172PD81723 (positive)
    A2AGsCGS21680, ATL-313, ATL-146e, UK-432097, compound 4g, sonedenoson, binodenoson, regadenosonKW6002, CSC, MSX-2, SYN-115, BIIB014, ST-1535, SCH442416, ZM241385, SCH58261, preladenant—
    A2BGs, GqNECA, Bay 60-6583PSB603, PSB-0788, PSB1115, ATL 802, LAS8096, MRS1754, CVT-6883, MRE -2029-F20—
    A3Gs, GqCF-101, CF-102, CF-502, CO 608,039, HEMADO, MRS 5151, IB-MECA, MRS5698KF26777, PSB-10, PSB-11, MRE-3008-F20, MRS1220,VUF5574, MRS1523, MRS1191LUF6000 (positive), LUF6096 (positive)

    • A317491, 5-[[[(3-phenoxyphenyl)methyl][(1S)-1,2,3,4-tetrahydro-1-naphthalenyl]amino]carbonyl]-1,2,4-benzenetricarboxylic acid sodium salt hydrate; A438079, 3-(5-(2,3-dichlorophenyl)-1H-tetrazol-1-yl)methyl pyridine hydrochloride hydrate; A740003, N-(1-{[(cyanoimino)(5-quinolinylamino) methyl] amino}-2,2-dimethylpropyl)-2-(3,4-dimethoxyphenyl)acetamide; A804598, N-Cyano-N′′-[(1S)-1-phenylethyl]-N′-5-quinolinyl-guanidine; A839977, 1-(2,3-dichlorophenyl)-N-[[2-(2-pyridinyloxy)phenyl]methyl]-1H-tetrazol-5-amine; ADPβS, adenosine 5-O-(2-thiodiphosphate); AF-219, 5-(2,4-diaminopyrimidin-5-yl)oxy-2-methoxy-4-propan-2-ylbenzenesulfonamide; AF-906, 2-[[4-amino-5-(5-iodo-4-methoxy-2-propan-2-ylphenoxy)pyrimidin-2-yl]amino]propane-1,3-diol; Ap5A, P1,P5-Di(adenosine-5′)pentaphosphate; AR-C67085, [[[[(2R,3S,4R,5R)-5-(6-amino-2-propylsulfanylpurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl]-dichloromethyl]phosphonic acid; AR-C 66096, 2-(propylthio)adenosine-5′-O-(β,γ-difluoromethylene)triphosphate tetrasodium salt; ARL66096, 2-(propylthio)adenosine-5′-O-(β,γ-difluoromethylene)triphosphate tetrasodium salt; ATL-146e, 4-{3-[6-amino-9-(5-ethylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl}-cyclohexanecarboxylic acid methyl ester; ATL-313, methyl 4-[3-[6-amino-9-[(2R,3R,4S,5S)-5-(cyclopropylcarbamoyl)-3,4-dihydroxyoxolan-2-yl]purin-2-yl]prop-2-ynyl]piperidine-1-carboxylate; ATPγS, adenosine-5′-(γ-thio)-triphosphate; AZD1283, ethyl 5-cyano-2-methyl-6-[4-[[[(phenylmethyl)sulfonyl]amino]carbonyl]-1-piperidinyl]-3-pyridinecarboxylate; 5-BDBD, 5-(3-bromophenyl)-1,3-dihydro-2H-benzofuro[3,2-e]-1,4-diazepin-2-one; BX-430, N-[2,6-dibromo-4-(1-methylethyl)phenyl]-N′-(3-pyridinyl)urea; BzATP, 2′(3′)-O-(4-benzoylbenzoyl)adenosine 5′-triphosphate triethylammonium; CCPA, 2-chloro-N6-cyclopentyladenosine; CF-502, [(1′R,2′R,3′S,4′R,5′S)-4-{2-chloro-6-[(3 chlorophenylmethyl)amino]purin-9-yl}-1-(methylaminocarbonyl)bicyclo[3.1.0]hexane-2,3-diol]; CHA, N6-cyclohexyl adenosine; 2-Cl-ADP(α-BH3), [[(2R,3S,4R,5R)-5-(6-amino-2-chloropurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methoxy phosphonooxyphosphoryl]boron(1-); CPA, N6-cyclopentyladenosine; CPFPX, 8-cyclopentyl-3-(3-fluoranylpropyl)-1-propyl-7H-purine-2,6-dione; CSC, 8-[(E)-2-(3-chlorophenyl)vinyl]-1,3,7-trimethyl-3,7-dihydro-1H-purine-2,6-dione; CVT-6883, 3-ethyl-3,9-dihydro-1-propyl-8-[1-[[3-(trifluoromethyl)phenyl]methyl]-1H-pyrazol-4-yl]-1H-purine-2,6-dione; CVT-6883, 3-ethyl-3,9-dihydro-1-propyl-8-[1-[[3-(trifluoromethyl)phenyl]methyl]-1H-pyrazol-4-yl]-1H-purine-2,6-dione; DPCPX, 8-cyclopentyl-1,3-dipropylxanthine; GR79236, N-[(1S,2S)-2-hydroxycyclopentyl]adenosine; GS9667, 5′-S-(2-fluorophenyl)-N-[(1R,2R)-2-hydroxycyclopentyl]-5′-thioadenosine; GW493838, (2S,3S,4R,5R)-2-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-{6-[(4-chloro-2-fluorophenyl)amino]-9H-purin-9-yl}oxolane-3,4-diol; HEMADO, 2-(1-hexynyl)-N-methyladenosine; HT-AMP, [(2R,3S,4R,5R)-5-(6-amino-2-hexylsulfanylpurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl dihydrogen phosphate; Ip5I, diinosine pentaphosphate; KF26777, (2-(4-bromophenyl)-7,8-dihydro-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one dihydrochloride); KN62, 4-[(2S)-2-[(5-isoquinolinylsulfonyl)methylamino]-3-oxo-3-(4-phenyl-1-piperazinyl)propyl] phenyl isoquinolinesulfonic acid ester; KW-3902, 1,3-dipropyl-8-(3-noradamantyl)xanthine, 8-(hexahydro-2,5-methanopentalen-3a(1H)-yl)-3,7-dihydro-1,3-dipropyl-1H-purine-2,6-dione; KW6002, (E)-8-(3,4-dimethoxystyryl)-1,3-diethyl-7-methylxanthine, 8-[(1E)-2-(3,4-dimethoxyphenyl)ethenyl]-1,3-diethyl-3,7-dihydro-7-methyl-1H-purine-2,6-dione; L-β,γ-meATP, l-beta,gamma-metilen ATP; 8MDP, 2,2′,2″,2′″-[[4,8-bis(hexahydro-1(2H)-azocinyl)pyrimido[5,4-d]pyrimidine-2,6-diyl]dinitrilo]tetrakisethanol; α,β-meATP, alpha, beta metilen ATP; 2′-Me-CCPA, 2′-metil 2-chloro-N6-cyclopentyladenosine; 2-MeSADP, [(2R,3S,4R,5R)-5-(6-amino-2-methylsulfanylpurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methylphosphono hydrogen phosphate; 2-MeSATP, 2-(methylthio)adenosine 5′-triphosphate tetrasodium salt; MRS1191, 3-ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate; MRS1220, 9-chloro-2-(2-furyl)-5-phenylacetylamino[1,2,4]-triazolo[1,5-c]quinazoline; MRS1523, 2,3-diethyl-4,5-dipropyl-6-phenylpyridine-3-thiocarboxylate-5-carboxylate; MRS1754, 8-[4-[[(4-cyano)phenylcarbamoylmethyl]oxy]phenyl]-1,3-di-(n-propyl)xanthine; MRS2179, 2′-deoxy-N6-methyladenosine 3′,5′-bisphosphate tetrasodium salt; MRS2211, 2-[(2-chloro-5-nitrophenyl)azo]-5-hydroxy-6-methyl-3-[(phosphonooxy)methyl]-4-pyridinecarboxaldehyde disodium salt; MRS2279, (1R*,2S*)-4-[2-chloro-6-(methylamino)-9H-purin-9-yl]-2-(phosphonooxy)bicyclo[3.1.0]hexane-1-methanol dihydrogen phosphate ester diammonium salt; MRS 2365, [[(1R,2R,3S,4R,5S)-4-[6-amino-2-(methylthio)-9H-purin-9-yl]-2,3dihydroxybicyclohex-1-yl]methyl] diphosphoric acid mono ester; MRS2567, 1-isothiocyanato-4-[2-(4-isothiocyanatophenyl)ethyl]benzene; MRS2578, 1,4-di[3-(3-isothiocyanatophenyl)thioureido]butane; MRS2603, [(2Z)-2-[(4-chloro-3-nitrophenyl)hydrazinylidene]-4-formyl-6-methyl-5-oxopyridin-3-yl]methyl dihydrogen phosphate; MRS2693, 5-iodouridine-5′-O-diphosphate trisodium salt; MRS2905, 2-thiouridine-5′-O-(α, β-methylene)diphosphate trisodium salt; MRS2957, P1-[5′(N4-methoxycytidyl)]-P3-(5′-uridyl)-triphosphate tri(triethylammonium) salt; MRS4062, [[(2R,3S,4R,5R)-3,4-dihydroxy-5-[2-oxo-4-(3-phenylpropoxyamino)pyrimidin-1-yl]oxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate; MRS 5151,6-(2-chloro-6-(((9-((1S,2R,3S,4R,5S)-3,4-dihydroxy 5(methylcarbamoyl)bicyclo[3.1.0]hexan-2-yl)-9H-purin-6-yl)amino)methyl)phenyl)hex-5-ynoic acid; MRS5698, (1S,2R,3S,4R,5S)-4-[6-[[(3-chlorophenyl)methyl]amino]-2-[2-(3,4-difluorophenyl)ethynyl]-9H-purin-9-yl]-2,3-dihydroxy-N-methylbicyclo[3.1.0]hexane-1carboxamide; NF023, 8,8′-[carbonylbis(imino-3,1-phenylenecarbonylimino)]bis-1,3,5-naphthalene-trisulphonic acid, hexasodium salt; NF157, 8,8′-[carbonylbis[imino-3,1-phenylenecarbonylimino(4-fluoro-3,1-phenylene)carbonylimino]]bis-1,3,5-naphthalenetrisulfonic acid hexasodium salt; NF 279, 8,8′-[carbonylbis(imino-4,1-phenylenecarbonylimino-4,1-phenylenecarbonylimino)]bis-1,3,5-naphthalenetrisulfonic acid hexasodium salt; NF340, 4,4′-(carbonylbis(imino-3,1-(4-methyl-phenylene)carbonylimino))bis(naphthalene-2,6-disulfonic acid) tetrasodium salt; NF449, 4,4′,4″,4′″-[carbonylbis(imino-5,1,3-benzenetriyl-bis(carbonylimino))]tetrakis-1,3-benzenedisulfonic acid, octasodium salt; NF546, 4,4′-(carbonylbis(imino-3,1-phenylene-carbonylimino-3,1-(4-methyl-phenylene)carbonylimino))-bis(1,3-xylene-alpha,alpha′;-diphosphonic acid tetrasodium salt; NF770, 5-methoxy-3-[[3-[[3-[[3-[[5-[(8-methoxy-3,6-disulfonaphthalen-2-yl)carbamoyl]-2 methylphenyl]carbamoyl]phenyl]carbamoylamino]benzoyl]amino]-4 methylbenzoyl]amino]naphthalene-2,7-disulfonic acid; NF778, 6,6-(carbonylbis(imino-3,1-phenylenecarbonylimino-3,1-(4-methyl-phenylene)carbonylimino))bis(1-methoxy-naphthalene-3,5-disulfonic acid) tetrasodium salt; (N)methanocarba UTP, [[4-(2,4-dioxopyrimidin-1-yl)-2,3-dihydroxy-1-bicyclo[3.1.0]hexanyl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate; PAPET-ATP, 2-[2-(4-aminophenyl)ethylthio]adenosine 5′-triphosphate; 3-phenacyl UDP, [(2R,3S,4R,5R)-5-(2,4-dioxo-3-phenacylpyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphono hydrogen phosphate; PPADS, pyridoxalphosphate-6-azophenyl-2′,4′-disulfonic acid; PPNDS, pyridoxal-5′-phosphate-6-(2′-naphthylazo-6′-nitro-4′,8′-disulfonate); PSB0474, 3-(2-oxo-2-phenylethyl)-uridine-5′-diphosphate disodium salt; PSB-0739, 1-amino-9,10-dihydro-9,10-dioxo-4-[[4-(phenylamino)-3-sulfophenyl]amino]-2-anthracenesulfonic acid sodium salt; PSB-0788, 8-[4-[4-(4-chlorobenzyl)piperazide-1-sulfonyl)phenyl]]-1-propylxanthine; PSB-10, 8-ethyl-1,4,7,8-tetrahydro-4-methyl-2-(2,3,5-trichlorophenyl)-5H-imidazo[2,1-i]purin-5-one monohydrochloride; PSB-10211, 1-amino-4-[3-[(4,6-dichloro-1,3,5-triazin-2-yl)amino]anilino]-9,10-dioxoanthracene-2-sulfonic acid; PSB-11, (8R)-8-ethyl-1,4,7,8-tetrahydro-4-5H-imidazo[2,1-i]purin-5-one hydrochloride; PSB1115, 4-(2,3,6,7-tetrahydro-2,6-dioxo-1-propyl-1H-purin-8-yl)-benzenesulfonic acid; PSB-12062, 10-[(4-methylphenyl)sulfonyl]-10H-phenoxazine; PSB-12379, N6-benzyl-α,β-methyleneadenosine 5′-diphosphate disodium salt; PSB36, 1-butyl-3-(3-hydroxypropyl)-8-(3-noradamantyl)xanthine,1-butyl-8-(hexahydro-2,5 methanopentalen-3a(1H)-yl)-3,9-dihydro-3-(3-hydroxypropyl)-1H-purine-2,6-dione; PSB603, 8-[4-[4-(4-chlorophenzyl)piperazide-1-sulfonyl)phenyl]]-1-propylxanthine; Ro 0437626, N-[(1R)-2-[[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]amino]-2-oxo-1-(4 thiazolylmethyl)ethyl]-1H-benzimidazole-2-carboxamide; R-PIA, (2R,3S,4R,5R)-2-(hydroxymethyl)-5-[6-[[(2R)-1-phenylpropan-2-yl]amino]purin-9-yl]oxolane-3,4-diol; SCH442416, 2-(2-furanyl)-7-[3-(4-methoxyphenyl)propyl]-7H-pyrazolo [4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine; SCH58261, 7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine; SLV320, trans-4-[(2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexanol; ST-1535, 2-butyl-9-methyl-8-(2H-1,2,3-triazol-2-yl)-9H-purin-6-amine; SYN-115, 4-hydroxy-N-[4-methoxy-7-(4-morpholinyl)-2-benzothiazolyl]-4-methyl-1-piperidinecarboxamide; TCPA, N6-cyclopentyl-2-(3-phenylaminocarbonyltriazene-1-yl)adenosine; 2-thioUDP, [(2R,3S,4R,5R)-3,4-dihydroxy-5-(4-oxo-2-sulfanylidenepyrimidin-1-yl)oxolan-2-yl]methyl phosphono hydrogen phosphate; 2-thioUTP, 2-thiouridine-5′-triphosphate; TNP-ATP, 2′,3′-O-(2,4,6-trinitrophenyl) adenosine 5′-triphosphate; UK-432097, (2S,3S,4R,5R)-5-{6-[(2,2-diphenylethyl)amino]-2-[(2-{N-[1-(pyridin-2-yl)piperidin-4-yl]-(C-hydroxycarbonimidoyl)amino}ethyl)carbamoyl]-9H-purin-9-yl}-N-ethyl-3,4-dihydroxyoxolane-2-carboximidic acid; VUF5574, N-(2-methoxyphenyl)-N′-[2-(3-pyridinyl)-4-quinazolinyl]-urea; WRC-0571, 5-[[9-methyl-8-[methyl(propan-2-yl)amino]purin-6-yl]amino]bicyclo[2.2.1]heptan-2-ol; ZM241385, 4-[2-(7-amino-2-(2-furyl)[1,2,4-triazolo[2,3-a] [1,3,5]triazin-5-yl-amino]ethyl phenol.

  • TABLE 2

    Commercially available blockers for purinergic enzymes and transporters

    Molecular TargetInhibitors
    CD39Sodium polyoxotungstate (POM-1), 1-amino-4-(4-chlorophenyl)aminoanthraquinone-2-sulfonic acid sodium salt (PSB-069)
    CD73Adenosine 5′-(α,β-methylene)diphosphate, N6-benzyl-α,β-methyleneadenosine 5′-diphosphate disodium salt (PSB-12379), 1-amino-4-(anthracen-2-ylamino)-9,10-dioxoanthracene-2-sulfonate (PSB-0963), N6-phenylethyl- adenosine-5′-O-[(phosphonomethyl)phosphonic acid] (PSB-12425),(((S)-(((2R,3S,4R,5R)-5-(6-(benzyloxy)-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phosphoryl)methyl)phosphonic acid (PSB-12431), (((S)-(((2R,3S,4R,5R)-5-(6-(benzylthio)-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phosphoryl)methyl)phosphonic acid (PSB-12553), quercetin
    CD38Carba-β-NAD, pseudocarba-β-NAD, luteolin, luteolinidin, kuromanin, 4,4′-dihydroxy-azobenzene (DHAB), ara-F-NAD, ara-NAD, deoxy NR, deoxy-MNR, ara-F-NMN
    Nucleoside transporters2,2′,2″,2‴-[[4,8-bis(hexahydro-1(2H)-azocinyl)pyrimido[5,4-d]pyrimidine-2,6-diyl]dinitrilo]tetrakisethanol (8MDP), cilostazol, dilazep, dipyridamole, 5-iodotubercidin, 6-S-[(4-nitrophenyl)methyl]-6-thioinosine (NBMPR), TC-T6000
    Adenosine deaminaseerythro-9-(2-Hydroxy-3-nonyl)adenine hydrochloride (EHNA), pentostatin, 1-deazaadenosine, cladribine

    • β-NAD, β-nicotinamide adenine di nucleotide; NBMPR, 6-S-[(4-nitrophenyl)methyl]-6-thioinosine; PSB-069, 1-amino-4-(4-chlorophenyl)aminoanthraquinone-2-sulfonic acid sodium salt; PSB-12431, (((S)-(((2R,3S,4R,5R)-5-(6-(benzyloxy)-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2 yl)methoxy)(hydroxy)phosphoryl)methyl)phosphonic acid; PSB-12553, (((S)-(((2R,3S,4R,5R)-5-(6-(benzylthio)-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phosphoryl)methyl)phosphonic acid; TC-T6000, 2,2′-[[4,8-bis[bis(2-methylpropyl)amino]pyrimido[5,4-d]pyrimidine-2,6-diyl]diimino]bis-ethanol.

  • TABLE 3

    miRNA involved in the modulation of the purinergic network

    Regulatory miRNATarget in the Purinergic PathwayBiologic EffectReferences
    P2X7miR-150InhibitionHuang et al. (2013)
    miR-186InhibitionZhou et al. (2008)
    miR-216bInhibitionZheng et al. (2014)
    miR-22InhibitionJimenez-Mateos et al. (2015)
    miR-21InhibitionBoldrini et al. (2015)
    miR-125bStimulationParisi et al. (2016)
    CD39miR-155StimulationLiu et al. (2015)
    CD73miR-422aInhibitionBonnin et al. (2016)
    miR-30 familyInhibitionXie et al. (2017)
    miR-340InhibitionWang et al. (2018b)
    miR-187InhibitionZhang et al. (2016)
    miR-193bInhibitionIkeda et al. (2012)
    A2AmiR-34bInhibitionVillar-Menendez et al. (2014)
    miR-214InhibitionZhao et al. (2015)
    miR-15InhibitionHeyn et al. (2012)
    miR-16InhibitionHeyn et al. (2012)
    A2BmiR-27bInhibitionKolachala et al. (2010)
    miR-128aInhibitionKolachala et al. (2010)
    miR-128bInhibitionKolachala et al. (2010)
    ADA 2miR-14b-3pInhibitionFulzele et al. (2015)
  • TABLE 4

    Effects of a pharmacological modulation of purine system in preclinical models of immune/inflammatory diseases

    Experimental ModelAnimalMolecular TargetLigandPharmacological EffectReferences
    Multiple Sclerosis
    Experimental autoimmune encephalomyelitis (EAE)C57BL/6 miceP2X7oATP (5 or 10 mg/kg/day), Brilliant Blue G (5 or 10 mg/kg/day)Attenuation of tissue damage and amelioration of neurologic consequences (increase in conduction latency) associated with EAEMatute et al. (2007)
    C57BL/6 miceP2Y12Clopidogrel (5, 15, 50 mg/kg/day), Ticagrelor (30 mg/kg/day)Amelioration of clinical symptomsQin et al. (2017)
    Reduction of leukocyte infiltration in the spinal cord
    Inhibition of Th17 differentiation
    C57BL/6 miceA2ASCH58261 (2 mg/kg/day)Protection of mice from EAE inductionMills et al. (2008)
    C57BL/6 miceA2ACGS21680 (0.01 or 0.05 mg/kg/day)Reduction of the severity of inflammation and tissue damageLiu et al. (2016)
    Reduction of Th1, Th2, and Th17 cells and an increase in Treg cells, with the reduction of IFN-γ, IL-4, and IL-17 release and the induction of TGF-β release
    C57BL/6 miceA2ACGS-21680 (50 µg/kg/day)Reduction of disease severity in EAE miceLiu et al. (2018)
    Reduction of spinal cord CD45+ cells infiltration
    Decrease of blood-brain barrier permeability
    C57BL/6 miceA2BCVT-6883 (0.3, 1, 3 mg/kg/day), MRS-1754 (1 mg/kg/day)Reduction of the peak severity and cumulative clinical scoreWei et al. (2013)
    Reduction of the percentage of Th17 and Th1 cells in the CD4+ population in the spleen
    Uveitis
    Immunization with the human interphotoreceptor retinoid-binding protein peptide IRBP1–20Female C57BL/6 (B6) miceP2X7OxATP i.p. injection of 300 μg/mouse every 3 daysReduction of Th17 autoreactive T cellsZhao et al. (2016)
    Female C57BL/6 (B6) miceAdenosine receptorsNECA i.p. injection of 100 ng/mouse(0 days postimmunization) suppressive effect on disease development and Th17 responsesLiang et al. (2014)
    (7 days postimmunization) enhanced disease activity and Th17 responses
    C57BL/6 J miceA2ACGS 21680 0.5 mg/kg given i.p. once a day for 3 daysAdministered at the peak of the disorder accelerated the resolution of diseaseLee et al. (2016)
    C57BL/6 miceA3CF101 10 μg/kg p.o., twice daily for 19 daysImprovement of uveitis clinical scores, amelioration of the pathologic manifestations of the disease and reduction of antigen-specific proliferation and cytokine production of autoreactive T cellsBar-Yehuda et al. (2011)
    Female C57BL/6 (B6) miceEndogenous adenosineADA 5U/mouse given i.p. for 22 daysSuppression of the course of EAU when given 8–14 days post-immunization and augmentation when given either before or after this periodLiang et al. (2016b)
    Myasthenia gravis
    Immunization with AChR R97‐116 peptideFemale Lewis ratsA2ACGS21680 0.5 mg/kg i.p. every 3 days for 29 days post EAMG inductionAmelioration of disease severity and decrease in the number of Th1 and Th2 cells while increasing the number of Treg cellsLi et al. (2012)
    Rheumatoid arthritis
    Freund’s adjuvant induced arthritisDBA/1J miceP2X7Suramin (30 mg/kg), A-438079 (5 mg/kg)Attenuation of joint damageFan et al. (2016)
    Reduction of paw edema and IL-17 concentration in synovial fluid
    Collagen-induced arthritisC57BL/6 miceA2A (pro-drug)2-(cyclohexylethylthio)adenosine 5′-monophosphate (0.5 mg/kg/min)Amelioration of clinical and histologic scoreFlogel et al. (2012)
    Inhibition of proteo-glycan depletion and cartilage matrix erosion
    Reduction of IL-1, IL-6, IFN-γ, MCP-1, and TNF in synovial fluid
    Freund’s adjuvant-induced arthritisLewis ratsA31-(methylaminocarbonyl)bicyclo[3.1.0]hexane-2,3-diol] (also named CF 502) (1, 10, and 100 μg/kg)Amelioration of clinical and histologic scoreOchaion et al. (2008)
    Reduction of PI3K, PKB/AKT, IKK, NF-κB, and TNF in paw extracts
    Reduction of GSK-3β, PARP, and β catenin in paw extracts
    Scleroderma
    Bleomycin-induced fibrosisMale C57BL/6 miceA2AZM241385 (50 mg/kg i.p. twice per day)Attenuation of bleomycin-induced dermal fibrosis (reduced punch biopsy skin thickness, lower skinfold thickness)Chan et al. (2006)
    Tcf/Lef:H2B-GFP miceA2AKW6002 (10 mg/kg once per day i.p)Reduction of skin thickness, skinfold thickness, breaking tension, dermal hydroxyproline content, myofibroblast accumulation, and collagen alignment in bleomycin-induced dermal fibrosisZhang et al. (2017a)
    C57BL/6J mice and TSK1 miceA2BC57BL/6J mice: GS-6201 (p.o for 15 days) TSK1 mice: GS-6201(p.o for 30 days)In C57BL/6J mice: reduction of dermal fibrosis and reduction of extracellular matrix molecule fibronectin and decreased number of alternatively activated macrophagesKarmouty-Quintana et al. (2018)
    In TSK1 mice: reduction of dermal fibrosis at the hyperdermal layer and reduction in hyperdermal layer thickness.
    Reduction of IL-6 and MCP-1 in the skin
    Psoriasis
    12-Otetradecanoylphorbol-13-acetateSwiss CD-1A2ACGS-21680 (5 µg per site)Reduction of epidermal hyperplasia and promotion of collagen synthesisArasa et al. (2014)
    Normalization of epidermal structure and enhancement of fibroblast proliferation in the dermis
    Reduction of chemotactic mediator expression and Nfκ-B inhibition
    Systemic lupus erythematosus
    Genetic modelMRL/lpr miceA2ACGS-21680 (0.4 mg/kg per day, i.p. for 8 wk)Reduction in proteinuria, blood urea, and creatinine as well as improvement in renal histologyZhang et al. (2011)
    Reduction of renal macrophage and T-cell infiltration
    Reduction of MCP-1, IFN-γ and MHC-II expression
    Reduction of serum anti-dsDNA and renal immune complex deposition. Inhibition of NFκB activation and suppression the of IFN-γ, MCP-1 and MHC- II expression in splenocytes
    Glomerulonephritis
    Antibody-mediated glomerulonephritisMale WKY ratsP2X7A-438079 (300 μmol/kg i.p. injection twice daily for 7 days)Reduction in fibrinoid necrosisTaylor et al. (2009)
    Reduction in proteinuria
    Reduction in glomerular macrophage infiltration
    Genetic modelMRL/lpr miceP2X7brilliant blue G (45.5 mg/kg i.p. injection every 48 h for 8 wk)Reduction of NLRP3/ASC/caspase 1 assembly, reduction of interleukin-1β releaseZhao et al. (2013)
    Reduction in the severity of nephritis and circulating anti-dsDNA antibodies.
    Reduction of the serum levels of IL-1β and IL-17 and in the Thl7:Treg cell ratio
    anti-GBM AbMale WKY ratsA2ACGS 21680 1.5 mg/kg i.p. twice a day for 5 daysReduction of damage to the kidneysGarcia et al. (2008)
    Suppression of the glomerular expression of the MDC/CCL22 chemokine and down-regulation of MIP-1α/CCL3, RANTES/CCL5, MIP-1β/CCL4, and MCP-1/CCL2 chemokines
    Increase of anti-inflammatory cytokines, IL-4 and IL-10
    Chronic obstructive pulmonary disease
    Smoke-induced lung inflammationC57/Bl6 miceP2X7KN62 (1 μM by mouth 30 min before each cigarette smoke exposure on days 1–3)Prevention of the lung parenchyma destructionLucattelli et al. (2011)
    Asthma
    OvalbuminBalb/c and C57BL/6 miceP2X45-BDBD (80 μl 100 μM, intratracheally before each of the three consecutive OVA-aerosol challenges)Reduction of broncho alveolar lavage fluid eosinophilia, peribronchial inflammation, Th2 cytokine production and bronchial hyperresponsivenessZech et al. (2016)
    Balb/c and C57BL/6 miceP2X7KN62 (10 μM, intratracheally before allergen challenge)Reduction of airway eosinophilia, goblet cell hyperplasia, and bronchial hyperresponsiveness to methacholineMuller et al. (2011)
    Reduction in allergic airway inflammation
    Balb/c and C57BL/6 miceP2Y1MRS2179: 30 mg/kg, MRS2500: 3 mg/kg administered intravenously 20 min before the start of allergen challengeReduction of leukocyte recruitment to the lungAmison et al. (2015)
    Female BALB/c miceA2ACGS-21680 (10 or 100 μg/kg intranasally, half an hour before and 3 h after the challenge)Inhibition of bronchoalveolar lavage fluid inflammatory cell influxBonneau et al. (2006)
    No effect on OVA-induced bronchoconstriction
    Genetical modelADA-deficient miceA2BCVT-6883 (1 mg/kg i.p. for 14 days)Reduction of immune cell number in the BAL fluid,Sun et al. (2006)
    Decreased production of pro-inflammatory cytokines and chemokines
    Attenuation of pulmonary fibrosis
    Inflammatory bowel diseases
    Trinitrobenzene sulfonic (TNBS) acidWistar ratsP2X7A740003 (16 mg/kg/day), Brilliant Blue G (40 mg/kg/day)Amelioration of clinical and histologic scoresMarques et al. (2014)
    Reduction of macrophage and T-cell tissue infiltration
    Reduction of tissue apoptosis
    Inhibition of NF-kappa B and MAP kinase activation
    Spontaneous ileitisSAMP1/YitFc mouseA2AATL-146e (0.1 μg · kg−1 · min−1)Decrease of the chronic inflammatory index and villus distortion indexOdashima et al. (2005)
    Reduction of TNF, IFN gamma, and IL- 4 in supernatants from cultures of mesenteric lymph node cells
    OxazoloneSprague-Dawley ratsA2APSB-0777 (0.4 mg/kg/day)Amelioration of microscopic damage scoreAntonioli et al. (2018a)
    Reduction of tissue TNF and oxidative stress
    Sodium dextran sulfate (DSS)NMRI miceA2ACGS 21680 (0.5 mg/kg/day)CGS 21680 was ineffective in ameliorating DSS-induced colitis in miceSelmeczy et al. (2007)
    C57BL/6 miceA2BATL-801 (10 mg/kg/day)Reduction of clinical symptoms, histologic scores, IL-6 levels and proliferation indicesKolachala et al. (2008a)
    Suppression of the inflammatory infiltrate into colonic mucosa and decrease of epithelial hyperplasia
    C57BL/6 miceA2BPSB1115 (1 mg/kg/day)Increase in severity of DSS colitisFrick et al. (2009)
    BALB/c miceA3IB MECA (1 or 3 mg/kg/day b.i.d.)Amelioration of clinical signs of colitisMabley et al. (2003)
    Reduction of tissue IL-1, IL-6, IL-12 MIP-1, MIP-2, MPO, and MDA levels
    Interleukin-10−/−C57BL/6 miceA3IB MECA (1 or 3 mg/kg/day b.i.d.)Reduction of tissue IL-1, IL-6, MIP-1, MIP-2, MPO, and MDA levelsMabley et al. (2003)
    Trinitrobenzene sulfonic (TNBS) acidSprague-Dawley ratsA3IB-MECA (1.5 mg/kg b.i.d.)Improvement of the clinical and histologic score, appetite, and weight gainGuzman et al. (2006)
    Reduction of free radical production
    Dinitrobenzene sulfonic (DNBS) acidSprague-Dawley ratsAdenosine deaminase4-amino-2-(2-hydroxy-1-decyl)pyrazole[3,4-d]pyrimidine (APP, 5, 15, or 45 micromol/kg) and erythro-9-(2-hydroxy-3-nonyl)adenine hydrochloride (EHNA, 10, 30, or 90 micromol/kg)Amelioration of systemic (food intake, body and spleen weight) and colonic [macroscopic/microscopic damage, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and malondialdehyde (MDA)] inflammatory parametersAntonioli et al. (2007)
    Antonioli et al. (2010a)
    interleukin-10−/−C57BL/6 miceAdenosine deaminasePentostatin (0.75 mg/kg)Improvement of the clinical and histologic scoreBrown et al. (2008a)
    Reduction of Th1 cytokines (IL-1β, IFN-γ, TNF, IL-6, CXCL10)

    • ATL-801, N-[5-(1-cyclopropyl-2,6-dioxo-3-propyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-pyridin-2-yl]-N-ethyl nicotinamide; ATL 802, N-(5-(1-cyclopropyl-2,6-dioxo-3-propyl-2,3,6,7-tetrahydro-1H-purin-8-yl)pyridin-2-yl)-N-methyl-6-(trifluoromethyl)nicotinamide; CGS 21680, 4-[2-[[6-amino-9-(N-ethyl-β-d-ribofuranuronamidosyl)-9H-purin-yl]amino]ethyl] benzene propanoic acid; MRS2500, (1R,2S,4S,5S)-4-[2-iodo-6-(methylamino)-9H-purin-9-yl]-2 (phosphonooxy)bicyclohexane-1-methanol dihydrogen phosphate ester.

  • TABLE 5

    Purinergic receptor ligands in clinical studies for treating inflammatory diseases

    DrugTargetAgonist or AntagonistDiseaseStatusCompanyReferences
    CE-224,535P2X7AntagonistRheumatoid arthritisPhase 2PfizerNCT00628095
    GSK1482160P2X7AntagonistInflammatory pain (arthritis)Phase 1Glaxo SmithKlineNCT00849134
    PBF-680A1AntagonistAsthmaPhase 1PalabiofarmaNCT01845181
    PBF-680A1AntagonistAsthmaPhase 2PalabiofarmaNCT02635945
    UK 432097A2AAgonistCOPDPhase 2PfizerNCT00430300
    PoclidenosonA3AgonistRheumatoid arthritisPhase 3CanFite PharmaNCT02647762
    PoclidenosonA3AgonistPsoriasisPhase 3CanFite PharmaNCT00428974
    PBF-677A3AgonistUlcerative colitisPhase 2PalabiofarmaNCT02639975
  • TABLE 6

    Expression of enzyme machinery, nucleoside transporters and purinergic receptors on immune cells and platelets

    Immune cell typesPlatelets
    Dendritic cellsMonocytesMacrophagesNeutrophilsMast cellsT cellsB cellsNK cells
    P2 ReceptorsP2X1++++++++
    P2X2++
    P2X3++
    P2X4++++++++
    P2X5++++++
    P2X6++
    P2X7++++++++
    P2Y1+++++++++
    P2Y2+++++++
    P2Y4+++++
    P2Y6+++++++
    P2Y11+++++
    P2Y12++++++
    P2Y13++++++
    P2Y14++++++
    Synthetic enzymesCD39+++++++++
    CD73+++
    CD38/CD203a++
    P1 ReceptorsA1++++
    A2A+++++++++
    A2B++++++++
    A3+++++++
    Catabolic enzymes and transportersAdenosine deaminase+++++
    Nucleoside transporters+ (CNTs)+ (CNTs)+ (ENT1, 2, 3) + (CNT1, 2)+ (ENT1) + (CNTs)+ (ENTs) + (CNTs)+ (ENTs) + (CNT2)+ (CNTs)

    • CD203a, ectonucleotide pyrophosphatase/phosphodiesterase 3.

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Review ArticleReview Article

Purinergic Signaling and Immune/Inflammatory Disorders

Luca Antonioli, Corrado Blandizzi, Pál Pacher and György Haskó
Pharmacological Reviews July 1, 2019, 71 (3) 345-382; DOI: https://doi.org/10.1124/pr.117.014878
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