Improvement of spinal non-viral IL-10 gene delivery by D-mannose as a transgene adjuvant to control chronic neuropathic pain

Journal of Neuroinflammation

Erin D Milligan²  James A Wallace³  Eugene Limanovich¹  Daniel R Moezzi³  Jenny L Wilkerson³  Audra A Kerwin³  Brandi N Bowman³  Lauren A Alberti³  Ellen C Dengler³ 

[1] Department of Anesthesiology and Critical Care Medicine, School of Medicine, University of New Mexico Health Sciences Center, 1 University of New Mexico, MSC10 6000, Albuquerque, NM 87106, USA;Department of Neurosciences, Health Sciences Center, School of Medicine, University of New Mexico, Albuquerque, NM 87131-5223, USA;Department of Neurosciences, UNM School of Medicine, University of New Mexico Health Sciences Center, 1 University of New Mexico, Albuquerque, NM 87131-0001, USA

关键词: Rat;    Allodynia;    Dexamethasone;    Intrathecal injection;    Immunofluorescence microscopy;    Sciatic nerve;    Interleukin-1β;    Cytokine;    M2 polarized;   

Others  :  804096
DOI  :  10.1186/1742-2094-11-92

 received in 2014-02-05, accepted in 2014-04-23,  发布年份 2014

【 摘 要 】

Background

Peri-spinal subarachnoid (intrathecal; i.t.) injection of non-viral naked plasmid DNA encoding the anti-inflammatory cytokine, IL-10 (pDNA-IL-10) suppresses chronic neuropathic pain in animal models. However, two sequential i.t. pDNA injections are required within a discrete 5 to 72-hour period for prolonged efficacy. Previous reports identified phagocytic immune cells present in the peri-spinal milieu surrounding the i.t injection site that may play a role in transgene uptake resulting in subsequent IL-10 transgene expression.

Methods

In the present study, we aimed to examine whether factors known to induce pro-phagocytic anti-inflammatory properties of immune cells improve i.t. IL-10 transgene uptake using reduced naked pDNA-IL-10 doses previously determined ineffective. Both the synthetic glucocorticoid, dexamethasone, and the hexose sugar, D-mannose, were factors examined that could optimize i.t. pDNA-IL-10 uptake leading to enduring suppression of neuropathic pain as assessed by light touch sensitivity of the rat hindpaw (allodynia).

Results

Compared to dexamethasone, i.t. mannose pretreatment significantly and dose-dependently prolonged pDNA-IL-10 pain suppressive effects, reduced spinal IL-1β and enhanced spinal and dorsal root ganglia IL-10 immunoreactivity. Macrophages exposed to D-mannose revealed reduced proinflammatory TNF-α, IL-1β, and nitric oxide, and increased IL-10 protein release, while IL-4 revealed no improvement in transgene uptake. Separately, D-mannose dramatically increased pDNA-derived IL-10 protein release in culture supernatants. Lastly, a single i.t. co-injection of mannose with a 25-fold lower pDNA-IL-10 dose produced prolonged pain suppression in neuropathic rats.

Conclusions

Peri-spinal treatment with D-mannose may optimize naked pDNA-IL-10 transgene uptake for suppression of allodynia, and is a novel approach to tune spinal immune cells toward pro-phagocytic phenotype for improved non-viral gene therapy.

【 授权许可】

   
2014 Dengler et al.; licensee BioMed Central Ltd.

【 图 表 】

Scheme 1

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

【 参考文献 】

• [1]Bouhassira D, Lanteri-Minet M, Attal N, Laurent B, Touboul C: Prevalence of chronic pain with neuropathic characteristics in the general population. Pain 2008, 136(3):380-387.
• [2]Torrance N, Smith BH, Bennett MI, Lee AJ: The epidemiology of chronic pain of predominantly neuropathic origin. Results from a general population survey. J Pain 2006, 7(4):281-289.
• [3]Chiang CY, Dostrovsky JO, Iwata K, Sessle BJ: Role of glia in orofacial pain. Neuroscientist 2011, 17(3):303-320.
• [4]Ji RR, Berta T, Nedergaard M: Glia and pain: is chronic pain a gliopathy? Pain 2013, 154(Suppl 1):S10-S28.
• [5]Milligan ED, Watkins LR: Pathological and protective roles of glia in chronic pain. Nat Rev Neurosci 2009, 10(1):23-36.
• [6]Hu P, Bembrick AL, Keay KA, McLachlan EM: Immune cell involvement in dorsal root ganglia and spinal cord after chronic constriction or transection of the rat sciatic nerve. Brain Behav Immun 2007, 21(5):599-616.
• [7]Takeda M, Takahashi M, Matsumoto S: Contribution of the activation of satellite glia in sensory ganglia to pathological pain. Neurosci Biobehav Rev 2009, 33(6):784-792.
• [8]Scholz J, Woolf CJ: The neuropathic pain triad: neurons, immune cells, and glia. Nat Neurosci 2007, 10(11):1361-1368.
• [9]Cao L, DeLeo JA: CNS-infiltrating CD4+ T lymphocytes contribute to murine spinal nerve transection-induced neuropathic pain. Eur J Immunol 2008, 38:448-458.
• [10]Echeverry S, Shi XQ, Rivest S, Zhang J: Peripheral nerve injury alters blood-spinal cord barrier functional and molecular integrity through a selective inflammatory pathway. J Neurosci 2011, 31(30):10819-10828.
• [11]White FA, Jung H, Miller RJ: Chemokines and the pathophysiology of neuropathic pain. Proc Natl Acad Sci U S A 2007, 104(51):20151-20158.
• [12]Zhang J, De Koninck Y: Spatial and temporal relationship between monocyte chemoattractant protein-1 expression and spinal glial activation following peripheral nerve injury. J Neurochem 2006, 97(3):772-783.
• [13]Zhang J, Shi XQ, Echeverry S, Mogil JS, De Koninck Y, Rivest S: Expression of CCR2 in both resident and bone marrow-derived microglia plays a critical role in neuropathic pain. J Neurosci 2007, 27(45):12396-12406.
• [14]Foey AD, Parry SL, Williams LM, Feldmann M, Foxwell BM, Brennan FM: Regulation of monocyte IL-10 synthesis by endogenous IL-1 and TNF- alpha: role of the p38 and p42/44 mitogen-activated protein kinases. J Immunol 1998, 160(2):920-928.
• [15]Ma W, Lim W, Gee K, Aucoin S, Nandan D, Kozlowski M, Diaz-Mitoma F, Kumar A: The p38 mitogen-activated kinase pathway regulates the human interleukin-10 promoter via the activation of Sp1 transcription factor in lipopolysaccharide-stimulated human macrophages. J Biol Chem 2001, 276(17):13664-13674.
• [16]Mizuno T, Sawada M, Marunouchi T, Suzumara A: Production of interleukin-10 by mouse glial cells in culture. Biochem Biophys Res Commun 1994, 205(3):1907-1915.
• [17]Moore KW, de Waal Malefy R, Coffman RL, O’Garra A: Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol 2001, 19:683-765.
• [18]Gonzalez P, Burgaya F, Acarin L, Peluffo H, Castellano B, Gonzalez B: Interleukin-10 and interleukin-10 receptor-I are upregulated in glial cells after an excitotoxic injury to the postnatal rat brain. J Neuropathol Exp Neurol 2009, 68(4):391-403.
• [19]Ledeboer A, Wierinckx A, Bol JG, Floris S, de Lavalette Renardel C, De Vries HE, van den Berg TK, Dijkstra CD, Tilders FJ, Van-dam AM: Regional and temporal expression patterns of interleukin-10, interleukin-10 receptor and adhesion molecules in the rat spinal cord during chronic relapsing EAE. J Neuroimmunol 2003, 136:94-103.
• [20]Milligan ED, Penzkover KR, Soderquist RG, Mahoney MJ: Spinal interleukin-10 therapy to treat peripheral neuropathic pain. Neuromodulation 2012, 15(6):520-526. discussion 526
• [21]Abraham KE, McMillen D, Brewer KL: The effects of endogenous interleukin-10 on gray matter damage and the development of pain behaviors following excitotoxic spinal cord injury in the mouse. Neuroscience 2004, 124(4):945-952.
• [22]Ledeboer AM, Jekich BM, Sloane EM, Mahoney JH, Langer SJ, Milligan ED, 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(5):686-698.
• [23]Plunkett JA, Yu CG, Jm E, Bethea JR, Yezierski RP: Effects of interleukin-10 (IL-10) on pain behavior and gene expression following excitotoxic spinal cord injury in the rat. Exp Neurol 2001, 168:144-154.
• [24]Sloane EM, Langer SJ, Jekich BM, Mahoney JH, Hughes TS, Seibert W, Johnson K, Chavez RA, Watkins LR, Leinwand LA, Milligan ED: Immunological priming potentiates non-viral anti-inflammatory gene therapy treatment of neuropathic pain. Gene Ther 2009, 1:1-13.
• [25]Soderquist RG, Milligan ED, Harrison JA, Chavez RA, Johnson KW, Watkins LR, Mahoney MJ: PEGylation of interleukin-10 for the mitigation of enhanced pain states. J Biomed Mater Res A 2010, 93(3):1169-1179.
• [26]Molet J, Pohl M: Gene-based approaches in pain research and exploration of new therapeutic targets and strategies. Eur J Pharmacol 2013, 716(1–3):129-141.
• [27]Goss JR, Goins WF, Glorioso JC: Gene therapy applications for the treatment of neuropathic pain. Expert Rev Neurother 2007, 7(5):487-506.
• [28]Huang L, Hung M-C, Wagner E: Nonviral Vectors for Gene Therapy. San Diego: Academic Press; 1999.
• [29]Milligan ED, Sloane EM, Langer SJ, Hughes TR, 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.
• [30]Sloane EM, Soderquist RG, Maier SF, Mahoney MJ, Watkins LR, Milligan ED: Long-term control of neuropathic pain in a non-viral gene therapy paradigm. Gene Ther 2009, 16(4):470-475.
• [31]Khalil IA, Kogure K, Akita H, Harashima H: Uptake pathways and subsequent intracellular trafficking in nonviral gene delivery. Pharmacol Rev 2006, 58(1):32-45.
• [32]McMenamin PG, Wealthall RJ, Deverall M, Cooper SJ, Griffin B: Macrophages and dendritic cells in the rat meninges and choroid plexus: three-dimentional localisation by environmental scanning electron microscopy and confocal microscopy. Cell Tissue Res 2003, 313:259-269.
• [33]Braun JS, Kaissling B, Hir LH, Zenker W: Cellular components of the immune barrier in the spinal meninges and dorsal root ganglia of the normal rat: immunohistochemical (MHC class II) and electron-microscopic observations. Cell Tissue Res 1993, 273:209-217.
• [34]Kreutzberg GW: Microglia: a sensor for pathological events in the CNS. Trends Neurosci 1996, 19:312-318.
• [35]Krieg AM: CpG motifs in bacterial DNA and their immune effects. Annu Rev Immunol 2002, 20:709-760.
• [36]Wang X, Wang C, Zeng J, Xu X, Hwang PY, Yee WC, Ng YK, Wang S: Gene transfer to dorsal root ganglia by intrathecal injection: effects on regeneration of peripheral nerves. Mol Ther 2005, 12(2):314-320.
• [37]Wang Y, Abel K, Lantz K, Krieg AM, McChesney MB, Miller CJ: The Toll-like receptor 7 (TLR7) agonist, imiquimod, and the TLR9 agonist, CpG ODN, induce antiviral cytokines and chemokines but do not prevent vaginal transmission of simian immunodeficiency virus when applied intravaginally to rhesus macaques. J Virol 2005, 79(22):14355-14370.
• [38]Yew NS, Cheng SH: Reducing the immunostimulatory activity of CpG-containing plasmid DNA vectors for non-viral gene therapy. Expert Opin Drug Deliv 2004, 1(1):115-125.
• [39]Gordon S: Alternative activation of macrophages. Nat Rev 2003, 3:23-35.
• [40]Martinez FO, Helming L, Gordon S: Alternative activation of macrophages: an immunologic functional perspective. Annu Rev Immunol 2009, 27:451-483.
• [41]Gratchev A, Schledzewski K, Guillot P, Goerdt S: Alternatively activated antigen-presenting cells: molecular repertoire, immune regulation, and healing. Skin Pharmacol Appl Skin Physiol 2001, 14(5):272-279.
• [42]Komohara Y, Ohnishi K, Kuratsu J, Takeya M: Possible involvement of the M2 anti-inflammatory macrophage phenotype in growth of human gliomas. J Pathol 2008, 216(1):15-24.
• [43]Lan YY, Wang Z, Raimondi G, Wu W, Colvin BL, de Creus A, Thomson AW: ‘Alternatively activated’ dendritic cells preferentially secrete IL-10, expand Foxp3 + CD4+ T cells, and induce long-term organ allograft survival in combination with CTLA4-Ig. J Immunol 2006, 177(9):5868-5877.
• [44]Ponomarev ED, Maresz K, Tan Y, Dittel BN: CNS-derived interleukin-4 is essential for the regulation of autoimmune inflammation and induces a state of alternative activation in microglial cells. J Neurosci 2007, 27(40):10714-10721.
• [45]Lingnau M, Hoflich C, Volk HD, Sabat R, Docke WD: Interleukin-10 enhances the CD14-dependent phagocytosis of bacteria and apoptotic cells by human monocytes. Hum Immunol 2007, 68(9):730-738.
• [46]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(5):841-854.
• [47]Wolfe D, Mata M, Fink DJ: A human trial of HSV-mediated gene transfer for the treatment of chronic pain. Gene Ther 2009, 16(4):455-460.
• [48]Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL: Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods 1994, 53:55-63.
• [49]Milligan ED, Mehmert KK, Hinde JL, Harvey LOJ, Martin D, Tracey KJ, Maier SF, Watkins LR: Thermal hyperalgesia and mechanical allodynia produced by intrathecal administration of the Human Immunodeficiency Virus-1 (HIV-1) envelope glycoprotein, gp120. Brain Res 2000, 861:105-116.
• [50]Harvey LOJ: Efficient estimation of sensory thresholds. Behav Res Methods Instrum Comput 1986, 18:623-632.
• [51]Milligan ED, O’Connor KA, Nguyen KT, Armstrong CB, Twining C, Gaykema R, Holguin A, Martin D, Maier SF, Watkins LR: Intrathecal HIV-1 envelope glycoprotein gp120 enhanced pain states mediated by spinal cord proinflammatory cytokines. J Neurosci 2001, 21:2808-2819.
• [52]Treutwein B, Strasburger H: Fitting the psychometric function. Percept Psychophys 1999, 61(1):87-106.
• [53]Bennett GJ, Xie KY: A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 1988, 33:87-107.
• [54]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 RA, Watkins LR: Controlling neuropathic pain by adeno-associated virus driven production of the anti-inflammatory cytokine, interleukin-10. Mol Pain 2005, 1:9-22. BioMed Central Full Text
• [55]Wilkerson JL, Gentry KR, Dengler EC, Wallace JA, Kerwin AA, Armijo LM, Kuhn MN, Thakur GA, Makriyannis A, Milligan ED: Intrathecal cannabilactone CB (2) R agonist, AM1710, controls pathological pain and restores basal cytokine levels. Pain 2012, 153(5):1091-1106.
• [56]Wilkerson JL, Gentry KR, Dengler EC, Wallace JA, Kerwin AA, Kuhn MN, Zvonok AM, Thakur GA, Makriyannis A, Milligan ED: Immunofluorescent spectral analysis reveals the intrathecal cannabinoid agonist, AM1241, produces spinal anti-inflammatory cytokine responses in neuropathic rats exhibiting relief from allodynia. Brain Behav 2012, 2(2):155-177.
• [57]Wallace JA, Romero AA, Gabaldon AM, Roe VA, Saavedra SL, Lobner J: Tyrosine hydroxylase-containing neurons in the spinal cord of the chicken. I. Development and analysis of catecholamine synthesis capabilities. Cell Mol Neurobiol 1996, 16(6):625-648.
• [58]Czimmerer Z, Varga T, Poliska S, Nemet I, Szanto A, Nagy L: Identification of novel markers of alternative activation and potential endogenous PPARgamma ligand production mechanisms in human IL-4 stimulated differentiating macrophages. Immunobiology 2012, 217(12):1301-1314.
• [59]Hunt AE, Williams LM, Lali FV, Foxwell BM: IL-4 regulation of p38 MAPK signalling is dependent on cell type. Cytokine 2002, 18(6):295-303.
• [60]Grubbs FE: Sample criteria for testing outlying observations. Ann Math Stat 1950, 21(1):27-58.
• [61]Tietjen GL, Moore RH: Some Grubbs-type statistics for the detection of outliers. Technometrics 1972, 14(3):583-597.
• [62]Costigan M, Moss A, Latremoliere A, Johnston C, Verma-Gandhu M, Herbert TA, Barrett L, Brenner GJ, Vardeh D, Woolf CJ, Fitzgerald M: T-Cell infiltration and signaling in the adult dorsal spinal cord is a major contributor to neuropathic pain-like hypersensitivity. J Neurosci 2009, 29(46):14415-14422.
• [63]Leger T, Grist J, D’Acquisto F, Clark AK, Malcangio M: Glatiramer acetate attenuates neuropathic allodynia through modulation of adaptive immune cells. J Neuroimmunol 2011, 234(1–2):19-26.
• [64]Sweitzer SM, Hickey WF, Rutkowski MD, Pahl JL, DeLeo JA: Focal peripheral nerve injury induces leukocyte trafficking into the central nervous system: potential relationship to neuropathic pain. Pain 2002, 100:163-170.
• [65]Ghosh TK, Mickelson DJ, Fink J, Solberg JC, Inglefield JR, Hook D, Gupta SK, Gibson S, Alkan SS: Toll-like receptor (TLR) 2-9 agonists-induced cytokines and chemokines: I Comparison with T cell receptor-induced responses. Cell Immunol 2006, 243(1):48-57.
• [66]Hughes TS, Langer SJ, Virtanen SI, Chavez RA, Watkins LR, Milligan ED, Leinwand LA: Immunogenicity of intrathecal plasmid gene delivery: cytokine release and effects on transgene expression. J Gene Med 2009, 11(9):782-790.
• [67]Barnes PJ: How corticosteroids control inflammation: Quintiles Prize Lecture 2005. Br J Pharmacol 2006, 148(3):245-254.
• [68]McMaster A, Ray DW: Drug insight: selective agonists and antagonists of the glucocorticoid receptor. Nat Clin Pract Endocrinol Metab 2008, 4(2):91-101.
• [69]Kim MH, Na HK, Kim YK, Ryoo SR, Cho HS, Lee KE, Jeon H, Ryoo R, Min DH: Facile synthesis of monodispersed mesoporous silica nanoparticles with ultralarge pores and their application in gene delivery. ACS Nano 2011, 5(5):3568-3576.
• [70]Go A, Ryu YK, Lee JW, Moon EY: Cell motility is decreased in macrophages activated by cancer cell-conditioned medium. Biomol Ther 2013, 21(6):481-486.
• [71]Filla MS, Schwinn MK, Nosie AK, Clark RW, Peters DM: Dexamethasone-associated cross-linked actin network formation in human trabecular meshwork cells involves beta3 integrin signaling. Invest Ophthalmol Vis Sci 2011, 52(6):2952-2959.
• [72]Luo BH, Carman CV, Springer TA: Structural basis of integrin regulation and signaling. Annu Rev Immunol 2007, 25:619-647.
• [73]Meinl E, Krumbholz M, Derfuss T, Junker A, Hohlfeld R: Compartmentalization of inflammation in the CNS: a major mechanism driving progressive multiple sclerosis. J Neurol Sci 2008, 274(1–2):42-44.
• [74]Ghosh MC, Baatar D, Collins G, Carter A, Indig F, Biragyn A, Taub DD: Dexamethasone augments CXCR4-mediated signaling in resting human T cells via the activation of the Src kinase Lck. Blood 2009, 113(3):575-584.
• [75]Viguerie N, Picard F, Hul G, Roussel B, Barbe P, Iacovoni JS, Valle C, Langin D, Saris WH: Multiple effects of a short-term dexamethasone treatment in human skeletal muscle and adipose tissue. Physiol Genomics 2012, 44(2):141-151.
• [76]Kossi J, Peltonen J, Ekfors T, Niinikoski J, Laato M: Effects of hexose sugars: glucose, fructose, galactose and mannose on wound healing in the rat. Eur Surg Res 1999, 31(1):74-82.
• [77]Xu XL, Xie QM, Shen YH, Jiang JJ, Chen YY, Yao HY, Zhou JY: Mannose prevents lipopolysaccharide-induced acute lung injury in rats. Inflamm Res 2008, 57(3):104-110.
• [78]Chieppa M, Bianchi G, Doni A, Del Prete A, Sironi M, Laskarin G, Monti P, Piemonti L, Biondi A, Mantovani A, Introna M, Allavena P: Cross-linking of the mannose receptor on monocyte-derived dendritic cells activates an anti-inflammatory immunosuppressive program. J Immunol 2003, 171(9):4552-4560.
• [79]Stein M, Keshav S, Harris N, Gordon S: Interleukin 4 potently enhances murine macrophage mannose receptor activity: a marker of alternative immunologic macrophage activation. J Exp Med 1992, 176(1):287-292.
• [80]Ruan GX, Chen YZ, Yao XL, Du A, Tang GP, Shen YQ, Tabata Y, Gao JQ: Macrophage mannose receptor-specific gene delivery vehicle for macrophage engineering. Acta Biomater 2014, 10(5):1847-1855.
• [81]Yin L, Song Z, Kim KH, Zheng N, Gabrielson NP, Cheng J: Non-viral gene delivery via membrane-penetrating, mannose-targeting supramolecular self-assembled nanocomplexes. Adv Mater 2013, 25(22):3063-3070.
• [82]Park IY, Kim IY, Yoo MK, Choi YJ, Cho MH, Cho CS: Mannosylated polyethylenimine coupled mesoporous silica nanoparticles for receptor-mediated gene delivery. Int J Pharm 2008, 359(1–2):280-287.
• [83]Sun X, Chen S, Han J, Zhang Z: Mannosylated biodegradable polyethyleneimine for targeted DNA delivery to dendritic cells. Int J Nanomedicine 2012, 7:2929-2942.
• [84]Tsuruta T, Inoue R, Nagino T, Nishibayashi R, Makioka Y, Ushida K: Role of the mannose receptor in phagocytosis of Enterococcus faecalis strain EC-12 by antigen-presenting cells. Microbiology 2013, 2(4):610-617.
• [85]Terayama R, Bando Y, Murakami K, Kato K, Kishibe M, Yoshida S: Neuropsin promotes oligodendrocyte death, demyelination and axonal degeneration after spinal cord injury. Neuroscience 2007, 148(1):175-187.
• [86]Yang H, Lu P, McKay HM, Bernot T, Keirstead H, Steward O, Gage FH, Edgerton VR, Tuszynski MH: Endogenous neurogenesis replaces oligodendrocytes and astrocytes after primate spinal cord injury. J Neurosci 2006, 26(8):2157-2166.
• [87]Milligan ED, Soderquist RG, Malone SM, Mahoney JH, Hughes TS, Langer SJ, Sloane EM, Maier SF, Leinwand LA, Watkins LR, Mahoney MJ: Intrathecal polymer-based interleukin-10* gene delivery for neuropathic pain. Neuron Glia Biol 2006, 2:293-308.
• [88]Dowdall T, Robinson I, Meert TF: Comparison of five different rat models of peripheral nerve injury. Pharmacol Biochem Behav 2005, 80(1):93-108.
• [89]Robinson I, Meert TF: Stability of neuropathic pain symptoms in partial sciatic nerve ligation in rats is affected by suture material. Neurosci Lett 2005, 373(2):125-129.
• [90]Hatashita S, Sekiguchi M, Kobayashi H, Konno S, Kikuchi S: Contralateral neuropathic pain and neuropathology in dorsal root ganglion and spinal cord following hemilateral nerve injury in rats. Spine (Phila Pa 1976) 2008, 33(12):1344-1351.
• [91]Cheng CF, Cheng JK, Chen CY, Lien CC, Chu D, Wang SY, Tsaur ML: Mirror-image pain is mediated by nerve growth factor produced from tumor necrosis factor alpha-activated satellite glia after peripheral nerve injury. Pain 2014, 155(5):906-920.
• [92]Racz I, Nadal X, Alferink J, Banos JE, Rehnelt J, Martin M, Pintado B, Gutierrez-Adan A, Sanguino E, Bellora N, Manzanares J, Zimmer A, Maldonado R: Interferon-gamma is a critical modulator of CB (2) cannabinoid receptor signaling during neuropathic pain. J Neurosci 2008, 28(46):12136-12145.
• [93]Schreiber KL, Beitz AJ, Wilcox GL: Activation of spinal microglia in a murine model of peripheral inflammation-induced, long-lasting contralateral allodynia. Neurosci Lett 2008, 440(1):63-67.
• [94]Koltzenburg M, Wall PD, McMahon SB: Does the right side know what the left is doing? Trends Neurosci 1999, 22(3):122-127.
• [95]Spataro LE, Sloane EM, Milligan ED, Wieseler-Frank J, Schoeniger D, Jekich BM, Barrientos RM, Maier SF, Watkins LR: Spinal gap junctions: potential involvement in pain facilitation. J Pain 2004, 5(7):392-405.
• [96]Wu Z, Zhang J, Nakanishi H: Leptomeningeal cells activate microglia and astrocytes to induce IL-10 production by releasing pro-inflammatory cytokines during systemic inflammation. J Neuroimmunol 2005, 167(1–2):90-98.
• [97]Burudi EM, Regnier-Vigouroux A: Regional and cellular expression of the mannose receptor in the post-natal developing mouse brain. Cell Tissue Res 2001, 303(3):307-317.
• [98]Burudi EM, Riese S, Stahl PD, Regnier-Vigouroux A: Identification and functional characterization of the mannose receptor in astrocytes. Glia 1999, 25(1):44-55.
• [99]Echeverry S, Shi XQ, Haw A, Liu H, Zhang ZW, Zhang J: Transforming growth factor-beta1 impairs neuropathic pain through pleiotropic effects. Mol Pain 2009, 5:16. BioMed Central Full Text
• [100]Costigan M, Scholz J, Woolf CJ: Neuropathic pain: a maladaptive response of the nervous system to damage. Annu Rev Neurosci 2009, 32:1-32.
• [101]Miraucourt LS, Dallel R, Voisin DL: Glycine inhibitory dysfunction turns touch into pain through PKCgamma interneurons. PLoS One 2007, 2(11):e1116.
• [102]Chen Y, Zhang X, Wang C, Li G, Gu Y, Huang LY: Activation of P2X7 receptors in glial satellite cells reduces pain through downregulation of P2X3 receptors in nociceptive neurons. Proc Natl Acad Sci U S A 2008, 105(43):16773-16778.
• [103]Milligan EM, Ledeboer A, Sloane EM, Maier SF, Busha DA, Watkins LR: Glially driven enhancement of pain and its control by anti-inflammatory cytokines. In Immune and Glial Regulation of Pain. Edited by De Leo JA, Sorkin LS, Watkins LR. Seattle: IASP Press; 2007.
• [104]van Hecke O, Austin SK, Khan RA, Smith BH, Torrance N: Neuropathic pain in the general population: a systematic review of epidemiological studies. Pain 2013, 155(4):654-662.
• [105]DeLeo JA, Sorkin LS, Watkins LR: Immune and Glial Regulation of Pain. Seattle: IASP Press; 2007.
• [106]Rest RF, Farrell CF, Naids FL: Mannose inhibits the human neutrophil oxidative burst. J Leukoc Biol 1988, 43(2):158-164.
• [107]Willenborg DO, Parish CR, Cowden WB: Inhibition of adjuvant arthritis in the rat by phosphosugars and the alpha-glucosidase inhibitor castanospermine. Immunol Cell Biol 1992, 70(Pt 6):369-377.
• [108]Xu X, Xie Q, Shen Y, Lu G, Yao H, Chen Y, Zhou J: Involvement of mannose receptor in the preventive effects of mannose in lipopolysaccharide-induced acute lung injury. Eur J Pharmacol 2010, 641(2–3):229-237.
• [109]East L, Isacke CM: The mannose receptor family. Biochim Biophys Acta 2002, 1572(2–3):364-386.
• [110]Engering AJ, Cella M, Fluitsma DM, Hoefsmit EC, Lanzavecchia A, Pieters J: Mannose receptor mediated antigen uptake and presentation in human dendritic cells. Adv Exp Med Biol 1997, 417:183-187.
• [111]Linehan SA, Martinez-Pomares L, Gordon S: Mannose receptor and scavenger receptor: two macrophage pattern recognition receptors with diverse functions in tissue homeostasis and host defense. Adv Exp Med Biol 2000, 479:1-14.
• [112]Stahl PD, Ezekowitz RA: The mannose receptor is a pattern recognition receptor involved in host defense. Curr Opin Immunol 1998, 10(1):50-55.
• [113]Tan MC, Mommaas AM, Drijfhout JW, Jordens R, Onderwater JJ, Verwoerd D, Mulder AA, van der Heiden AN, Scheidegger D, Oomen LC, Ottenhoff TH, Tulp A, Neefjes JJ, Koning F: Mannose receptor-mediated uptake of antigens strongly enhances HLA class II-restricted antigen presentation by cultured dendritic cells. Eur J Immunol 1997, 27(9):2426-2435.
• [114]Lewis CA, Solomon JN, Rossi FM, Krieger C: Bone marrow-derived cells in the central nervous system of a mouse model of amyotrophic lateral sclerosis are associated with blood vessels and express CX (3) CR1. Glia 2009, 57(13):1410-1419.
• [115]Hirai T, Uchida K, Nakajima H, Guerrero AR, Takeura N, Watanabe S, Sugita D, Yoshida A, Johnson WE, Baba H: The prevalence and phenotype of activated microglia/macrophages within the spinal cord of the hyperostotic mouse (twy/twy) changes in response to chronic progressive spinal cord compression: implications for human cervical compressive myelopathy. PLoS One 2013, 8(5):e64528.
• [116]Liu C, Li Y, Yu J, Feng L, Hou S, Liu Y, Guo M, Xie Y, Meng J, Zhang H, Xiao B, Ma C: Targeting the shift from M1 to M2 macrophages in experimental autoimmune encephalomyelitis mice treated with fasudil. PLoS One 2013, 8(2):e54841.
• [117]Vogel DY, Vereyken EJ, Glim JE, Heijnen PD, Moeton M, van der Valk P, Amor S, Teunissen CE, van Horssen J, Dijkstra CD: Macrophages in inflammatory multiple sclerosis lesions have an intermediate activation status. J Neuroinflammation 2013, 10:35. BioMed Central Full Text
• [118]Lee SJ, Evers S, Roeder D, Parlow AF, Risteli J, Risteli L, Lee YC, Feizi T, Langen H, Nussenzweig MC: Mannose receptor-mediated regulation of serum glycoprotein homeostasis. Science 2002, 295(5561):1898-1901.
• [119]Pontow SE, Kery V, Stahl PD: Mannose receptor. Int Rev Cytol 1992, 137B:221-244.
• [120]Grace PM, Hutchinson MR, Maier SF, Watkins LR: Pathological pain and the neuroimmune interface. Nat Rev Immunol 2014, 14:217-231.