IL-10 mediated by herpes simplex virus vector reduces neuropathic pain induced by HIV gp120 combined with ddC in rats

Molecular Pain

Shuanglin Hao¹  David A Lubarsky¹  Keith A Candiotti¹  Roy C Levitt²  Shue Liu¹  Wan Huang¹  Wenwen Zheng¹ 

[1] Department of Anesthesiology, University of Miami Miller School of Medicine, 1550 NW 10th Ave, Fox BLDG, Rm 304C, Miami, FL 33136, USA;Veterans Affairs Medical Center, Miami, FL 33136, USA

关键词: and Gene therapy;    IL-10;    ddC;    gp120;    Neuropathic pain;    HIV;   

Others  :  1161780
DOI  :  10.1186/1744-8069-10-49

 received in 2014-04-29, accepted in 2014-07-02,  发布年份 2014

【 摘 要 】

Background

HIV-associated sensory neuropathy affects over 50% of HIV patients and is a common peripheral nerve complication of HIV infection and highly active antiretroviral therapy (HAART). Evidence shows that painful HIV sensory neuropathy is influenced by neuroinflammatory events that include the proinflammatory molecules, MAP Kinase, tumor necrosis factor-α (TNFα), stromal cell-derived factor 1-α (SDF1α), and C-X-C chemokine receptor type 4 (CXCR4). However, the exact mechanisms of painful HIV sensory neuropathy are not known, which hinders our ability to develop effective treatments. In this study, we investigated whether inhibition of proinflammatory factors reduces the HIV-associated neuropathic pain state.

Results

Neuropathic pain was induced by peripheral HIV coat protein gp120 combined with 2′,3′-dideoxycytidine (ddC, one of the nucleoside reverse transcriptase inhibitors (NRTIs)). Mechanical threshold was tested using von Frey filament fibers. Non-replicating herpes simplex virus (HSV) vectors expressing interleukin 10 (IL10) were inoculated into the hindpaws of rats. The expression of TNFα, SDF1α, and CXCR4 in the lumbar spinal cord and L4/5 dorsal root ganglia (DRG) was examined using western blots. IL-10 expression mediated by the HSV vectors resulted in a significant elevation of mechanical threshold. The anti-allodynic effect of IL-10 expression mediated by the HSV vectors lasted more than 3 weeks. The area under the effect-time curves (AUC) in mechanical threshold in rats inoculated with the HSV vectors expressing IL-10, was increased compared with the control vectors, indicating antinociceptive effect of the IL-10 vectors. The HSV vectors expressing IL-10 also concomitantly reversed the upregulation of p-p38, TNFα, SDF1α, and CXCR4 induced by gp120 in the lumbar spinal dorsal horn and/or the DRG at 2 and/or 4 weeks.

Conclusion

The blocking of the signaling of these proinflammatory molecules is able to reduce HIV-related neuropathic pain, which provide a novel mechanism-based approach to treating HIV-associated neuropathic pain using gene therapy.

【 授权许可】

   
2014 Zheng et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Soderquist RG, Sloane EM, Loram LC, Harrison JA, Dengler EC, Johnson SM, Amer LD, Young CS, Lewis MT, Poole S, Frank MG, Watkins LR, Milligan ED, Mahoney MJ: Release of plasmid DNA-encoding IL-10 from PLGA microparticles facilitates long-term reversal of neuropathic pain following a single intrathecal administration. Pharm Res 2010, 27:841-854.
• [2]Gabbai AA, Castelo A, Oliveira AS: HIV peripheral neuropathy. Handb Clin Neurol 2013, 115:515-529.
• [3]Hao S, Mata M, Glorioso JC, Fink DJ: Gene transfer to interfere with TNFalpha signaling in neuropathic pain. Gene Ther 2007, 14:1010-1016.
• [4]Zheng W, Ouyang H, Zheng X, Liu S, Mata M, Fink DJ, Hao S: Glial TNFalpha in the spinal cord regulates neuropathic pain induced by HIV gp120 application in rats. Mol Pain 2011, 7:40.
• [5]Hao S: The Molecular and Pharmacological Mechanisms of HIV-Related Neuropathic Pain. Curr Neuropharmacol 2013, 11:499-512.
• [6]Homma Y, Brull SJ, Zhang JM: A comparison of chronic pain behavior following local application of tumor necrosis factor alpha to the normal and mechanically compressed lumbar ganglia in the rat. Pain 2002, 95:239-246.
• [7]Narita M, Shimamura M, Imai S, Kubota C, Yajima Y, Takagi T, Shiokawa M, Inoue T, Suzuki M, Suzuki T: Role of interleukin-1beta and tumor necrosis factor-alpha-dependent expression of cyclooxygenase-2 mRNA in thermal hyperalgesia induced by chronic inflammation in mice. Neuroscience 2008, 152:477-486.
• [8]Zhou Z, Peng X, Hao S, Fink DJ, Mata M: HSV-mediated transfer of interleukin-10 reduces inflammatory pain through modulation of membrane tumor necrosis factor alpha in spinal cord microglia. Gene Ther 2008, 15:183-190.
• [9]Ji RR, Samad TA, Jin SX, Schmoll R, Woolf CJ: p38 MAPK activation by NGF in primary sensory neurons after inflammation increases TRPV1 levels and maintains heat hyperalgesia. Neuron 2002, 36:57-68.
• [10]Schafers M, Svensson CI, Sommer C, Sorkin LS: Tumor necrosis factor-alpha induces mechanical allodynia after spinal nerve ligation by activation of p38 MAPK in primary sensory neurons. J Neurosci 2003, 23:2517-2521.
• [11]Mocchetti I, Campbell LA, Harry GJ, Avdoshina V: When human immunodeficiency virus meets Chemokines and microglia: neuroprotection or neurodegeneration? J Neuroimmune Pharmacol 2012, 8:14.
• [12]Keswani SC, Polley M, Pardo CA, Griffin JW, McArthur JC, Hoke A: Schwann cell chemokine receptors mediate HIV-1 gp120 toxicity to sensory neurons. Ann Neurol 2003, 54:287-296.
• [13]Catani MV, Corasaniti MT, Navarra M, Nistico G, Finazzi-Agro A, Melino G: gp120 induces cell death in human neuroblastoma cells through the CXCR4 and CCR5 chemokine receptors. J Neurochem 2000, 74:2373-2379.
• [14]Huang W, Zheng W, Liu S, Zeng W, Levitt RC, Candiotti KA, Lubarsky DA, Hao S: HSV-mediated p55TNFSR reduces neuropathic pain induced by HIV gp120 in rats through CXCR4 activity. Gene Ther 2014, 21:328-336.
• [15]Bhangoo SK, Ren D, Miller RJ, Chan DM, Ripsch MS, Weiss C, McGinnis C, White FA: CXCR4 chemokine receptor signaling mediates pain hypersensitivity in association with antiretroviral toxic neuropathy. Brain Behav Immun 2007, 21:581-591.
• [16]Bhangoo SK, Ripsch MS, Buchanan DJ, Miller RJ, White FA: Increased chemokine signaling in a model of HIV1-associated peripheral neuropathy. Mol Pain 2009, 5:48.
• [17]Huang W, Zheng W, Ouyang H, Yi H, Liu S, Zeng W, Levitt RC, Candiotti KA, Lubarsky DA, Hao S: Mechanical allodynia induced by nucleoside reverse transcriptase inhibitor is suppressed by p55TNFSR mediated by HSV through SDF1α/CXCR4 system in rats. Anesth Analg 2014, 118:671-680.
• [18]Haddad JJ, Saade NE, Safieh-Garabedian B: Interleukin-10 and the regulation of mitogen-activated protein kinases: are these signalling modules targets for the anti-inflammatory action of this cytokine? Cell Signal 2003, 15:255-267.
• [19]Sawada M, Suzumura A, Hosoya H, Marunouchi T, Nagatsu T: Interleukin-10 inhibits both production of cytokines and expression of cytokine receptors in microglia. J Neurochem 1999, 72:1466-1471.
• [20]Pahan K, Khan M, Singh I: Interleukin-10 and interleukin-13 inhibit proinflammatory cytokine-induced ceramide production through the activation of phosphatidylinositol 3-kinase. J Neurochem 2000, 75:576-582.
• [21]Cassatella MA, Meda L, Bonora S, Ceska M, Constantin G: Interleukin 10 (IL-10) inhibits the release of proinflammatory cytokines from human polymorphonuclear leukocytes. Evidence for an autocrine role of tumor necrosis factor and IL-1 beta in mediating the production of IL-8 triggered by lipopolysaccharide. J Exp Med 1993, 178:2207-2211.
• [22]Howard M, O’Garra A: Biological properties of interleukin 10. Immunol Today 1992, 13:198-200.
• [23]Milligan ED, Sloane EM, Langer SJ, Hughes TS, Jekich BM, Frank MG, Mahoney JH, Levkoff LH, Maier SF, Cruz PE, Flotte TR, Johnson KW, Mahoney MM, Chavez RA, Leinwand LA, Watkins LR: Repeated intrathecal injections of plasmid DNA encoding interleukin-10 produce prolonged reversal of neuropathic pain. Pain 2006, 126:294-308.
• [24]Milligan E, Zapata V, Schoeniger D, Chacur M, Green P, Poole S, Martin D, Maier SF, Watkins LR: An initial investigation of spinal mechanisms underlying pain enhancement induced by fractalkine, a neuronally released chemokine. Eur J Neurosci 2005, 22:2775-2782.
• [25]Milligan ED, Sloane EM, Langer SJ, Cruz PE, Chacur M, Spataro L, Wieseler-Frank J, Hammack SE, Maier SF, Flotte TR, Forsayeth JR, Leinwand LA, Chavez R, Watkins LR: Controlling neuropathic pain by adeno-associated virus driven production of the anti-inflammatory cytokine, interleukin-10. Mol Pain 2005, 1:9.
• [26]Antunes bras J, Becker C, Bourgoin S, Lombard M, Cesselin F, Hamon M, Pohl M: Met-enkephalin is preferentially transported into the peripheral processes of primary afferent fibres in both control and HSV1-driven proenkephalin A overexpressing rats. Neuroscience 2001, 103:1073-1083.
• [27]Lau D, Harte SE, Morrow TJ, Wang S, Mata M, Fink DJ: Herpes simplex virus vector-mediated expression of interleukin-10 reduces below-level central neuropathic pain after spinal cord injury. Neurorehabil Neural Repair 2012, 26:889-897.
• [28]Herzberg U, Sagen J: Peripheral nerve exposure to HIV viral envelope protein gp120 induces neuropathic pain and spinal gliosis. J Neuroimmunol 2001, 116:29-39.
• [29]Wallace VC, Blackbeard J, Segerdahl AR, Hasnie F, Pheby T, McMahon SB, Rice AS: Characterization of rodent models of HIV-gp120 and anti-retroviral-associated neuropathic pain. Brain 2007, 130:2688-2702.
• [30]Zheng X, Ouyang H, Liu S, Mata M, Fink DJ, Hao S: TNFalpha is involved in neuropathic pain induced by nucleoside reverse transcriptase inhibitor in rats. Brain Behav Immun 2011, 25:1668-1676.
• [31]Joseph EK, Chen X, Khasar SG, Levine JD: Novel mechanism of enhanced nociception in a model of AIDS therapy-induced painful peripheral neuropathy in the rat. Pain 2004, 107:147-158.
• [32]Jin SX, Zhuang ZY, Woolf CJ, Ji RR: p38 mitogen-activated protein kinase is activated after a spinal nerve ligation in spinal cord microglia and dorsal root ganglion neurons and contributes to the generation of neuropathic pain. J Neurosci 2003, 23:4017-4022.
• [33]Egea V, von Baumgarten L, Schichor C, Berninger B, Popp T, Neth P, Goldbrunner R, Kienast Y, Winkler F, Jochum M, Ries C: TNF-alpha respecifies human mesenchymal stem cells to a neural fate and promotes migration toward experimental glioma. Cell Death Differ 2011, 18:853-863.
• [34]Ji RR, Gereau RW, Malcangio M, Strichartz GR: MAP kinase and pain. Brain Res Rev 2009, 60:135-148.
• [35]Medders KE, Sejbuk NE, Maung R, Desai MK, Kaul M: Activation of p38 MAPK is required in monocytic and neuronal cells for HIV glycoprotein 120-induced neurotoxicity. J Immunol 2010, 185:4883-4895.
• [36]Yao H, Allen JE, Zhu X, Callen S, Buch S: Cocaine and human immunodeficiency virus type 1 gp120 mediate neurotoxicity through overlapping signaling pathways. J Neurovirol 2009, 15:164-175.
• [37]Milligan ED, O’Connor KA, Armstrong CB, Hansen MK, Martin D, Tracey KJ, Maier SF, Watkins LR: Systemic administration of CNI-1493, a p38 mitogen-activated protein kinase inhibitor, blocks intrathecal human immunodeficiency virus-1 gp120-induced enhanced pain states in rats. J Pain 2001, 2:326-333.
• [38]Merrill JE, Chen IS: HIV-1, macrophages, glial cells, and cytokines in AIDS nervous system disease. FASEB J 1991, 5:2391-2397.
• [39]Grimaldi LM, Martino GV, Franciotta DM, Brustia R, Castagna A, Pristera R, Lazzarin A: Elevated alpha-tumor necrosis factor levels in spinal fluid from HIV-1-infected patients with central nervous system involvement. Ann Neurol 1991, 29:21-25.
• [40]de Larranaga GF, Petroni A, Deluchi G, Alonso BS, Benetucci JA: Viral load and disease progression as responsible for endothelial activation and/or injury in human immunodeficiency virus-1-infected patients. Blood Coagul Fibrinolysis 2003, 14:15-18.
• [41]Shi Y, Gelman BB, Lisinicchia JG, Tang SJ: Chronic-pain-associated astrocytic reaction in the spinal cord dorsal horn of human immunodeficiency virus-infected patients. J Neurosci 2012, 32:10833-10840.
• [42]Tyor WR, Glass JD, Griffin JW, Becker PS, McArthur JC, Bezman L, Griffin DE: Cytokine expression in the brain during the acquired immunodeficiency syndrome. Ann Neurol 1992, 31:349-360.
• [43]Mocroft A, Ledergerber B, Katlama C, Kirk O, Reiss P, d’Arminio Monforte A, Knysz B, Dietrich M, Phillips AN, Lundgren JD, Euro S: Decline in the AIDS and death rates in the EuroSIDA study: an observational study. Lancet 2003, 362:22-29.
• [44]Bacellar H, Munoz A, Miller EN, Cohen BA, Besley D, Selnes OA, Becker JT, McArthur JC: Temporal trends in the incidence of HIV-1-related neurologic diseases: Multicenter AIDS Cohort Study, 1985–1992. Neurology 1994, 44:1892-1900.
• [45]Manji H: Neuropathy in HIV infection. Curr Opin Neurol 2000, 13:589-592.
• [46]Williams R, Dhillon NK, Hegde ST, Yao H, Peng F, Callen S, Chebloune Y, Davis RL, Buch SJ: Proinflammatory cytokines and HIV-1 synergistically enhance CXCL10 expression in human astrocytes. Glia 2009, 57:734-743.
• [47]Oh SB, Tran PB, Gillard SE, Hurley RW, Hammond DL, Miller RJ: Chemokines and glycoprotein120 produce pain hypersensitivity by directly exciting primary nociceptive neurons. J Neurosci 2001, 21:5027-5035.
• [48]Miller RJ, Jung H, Bhangoo SK, White FA: Cytokine and chemokine regulation of sensory neuron function. Handb Exp Pharmacol 2009, 194:417-449.
• [49]Hesselgesser J, Halks-Miller M, DelVecchio V, Peiper SC, Hoxie J, Kolson DL, Taub D, Horuk R: CD4-independent association between HIV-1 gp120 and CXCR4: functional chemokine receptors are expressed in human neurons. Curr Biol 1997, 7:112-121.
• [50]Denoyer A, Godefroy D, Célérier I, Frugier J, Degardin J, Harrison JK, Brignole-Baudouin F, Picaud S, Baleux F, Sahel JA, Rostène W, Baudouin C: CXCR3 antagonism of SDF-1(5–67) restores trabecular function and prevents retinal neurodegeneration in a rat model of ocular hypertension. PLoS One 2012, 7:e37873.
• [51]Krishnamurthy P, Thal M, Verma S, Hoxha E, Lambers E, Ramirez V, Qin G, Losordo D, Kishore R: Interleukin-10 deficiency impairs bone marrow-derived endothelial progenitor cell survival and function in ischemic myocardium. Circ Res 2011, 109:1280-1289.
• [52]Jinquan T, Quan S, Jacobi HH, Madsen HO, Glue C, Skov PS, Malling HJ, Poulsen LK: CXC chemokine receptor 4 expression and stromal cell-derived factor-1alpha-induced chemotaxis in CD4+ T lymphocytes are regulated by interleukin-4 and interleukin-10. Immunology 2000, 99:402-410.
• [53]Vale ML, Marques JB, Moreira CA, Rocha FA, Ferreira SH, Poole S, Cunha FQ, Ribeiro RA: Antinociceptive effects of interleukin-4, -10, and -13 on the writhing response in mice and zymosan-induced knee joint incapacitation in rats. J Pharmacol Exp Ther 2003, 304:102-108.
• [54]Milligan ED, Langer SJ, Sloane EM, He L, Wieseler-Frank J, O’Connor K, Martin D, Forsayeth JR, Maier SF, Johnson K, Chavez RA, Leinwand LA, Watkins LR: Controlling pathological pain by adenovirally driven spinal production of the anti-inflammatory cytokine, interleukin-10. Eur J Neurosci 2005, 21:2136-2148.
• [55]Poole S, Cunha FQ, Selkirk S, Lorenzetti BB, Ferreira SH: Cytokine-mediated inflammatory hyperalgesia limited by interleukin-10. Br J Pharmacol 1995, 115:684-688.
• [56]Ledeboer A, Jekich BM, Sloane EM, Mahoney JH, Langer SJ, Milligan ED, Martin D, Maier SF, Johnson KW, Leinwand LA, Chavez RA, Watkins LR: Intrathecal interleukin-10 gene therapy attenuates paclitaxel-induced mechanical allodynia and proinflammatory cytokine expression in dorsal root ganglia in rats. Brain Behav Immun 2007, 21:686-698.
• [57]Storek B, Reinhardt M, Wang C, Janssen WG, Harder NM, Banck MS, Morrison JH, Beutler AS: Sensory neuron targeting by self-complementary AAV8 via lumbar puncture for chronic pain. Proc Natl Acad Sci U S A 2008, 105:1055-1060.
• [58]Zhou Z, Peng X, Insolera R, Fink DJ, Mata M: IL-10 promotes neuronal survival following spinal cord injury. Exp Neurol 2009, 220:183-190.