Advertisement

IFNβ Treatment Inhibits Nerve Injury-induced Mechanical Allodynia and MAPK Signaling By Activating ISG15 in Mouse Spinal Cord

  • Su Liu
    Affiliations
    SUSTech Center for Pain Medicine, Medical School, Southern University of Science and Technology, Shenzhen, Guangdong, China

    Department of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu, China
    Search for articles by this author
  • Stephen Karaganis
    Affiliations
    SUSTech Center for Pain Medicine, Medical School, Southern University of Science and Technology, Shenzhen, Guangdong, China

    Department of Life, Earth and Environmental Sciences, West Texas A&M University, Amarillo, Texas
    Search for articles by this author
  • Ru-Fan Mo
    Affiliations
    SUSTech Center for Pain Medicine, Medical School, Southern University of Science and Technology, Shenzhen, Guangdong, China
    Search for articles by this author
  • Xiao-Xiao Li
    Affiliations
    Department of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu, China
    Search for articles by this author
  • Ruo-Xin Wen
    Affiliations
    SUSTech Center for Pain Medicine, Medical School, Southern University of Science and Technology, Shenzhen, Guangdong, China
    Search for articles by this author
  • Xue-Jun Song
    Correspondence
    Address reprint requests to Xue-Jun Song, MD, PhD, Southern University of Science and Technology, Shenzhen, Guangdong, China.
    Affiliations
    SUSTech Center for Pain Medicine, Medical School, Southern University of Science and Technology, Shenzhen, Guangdong, China
    Search for articles by this author
Published:November 27, 2019DOI:https://doi.org/10.1016/j.jpain.2019.11.010

      Highlights

      • Intrathecal interferon β (IFNβ) attenuates mechanical allodynia without behavioral deficits.
      • Interferon-stimulated gene 15 (ISG15) is induced by IFNβ in the spinal cord and mediates analgesic effects.
      • IFNβ mediated analgesia and induction of ISG15 is potentiated in UBP43−/− mice.
      • IFNβ treatment inhibits MAPK signaling by ISG15 activation.

      Abstract

      Neuropathic pain is difficult to treat and remains a major clinical challenge worldwide. While the mechanisms which underlie the development of neuropathic pain are incompletely understood, interferon signaling by the immune system is known to play a role. Here, we demonstrate a role for interferon β (IFNβ) in attenuating mechanical allodynia induced by the spared nerve injury in mice. The results show that intrathecal administration of IFNβ (dosages up to 5,000 U) produces significant, transient, and dose-dependent attenuation of mechanical allodynia without observable effects on motor activity or feeding behavior, as is common with IFN administration. This analgesic effect is mediated by the ubiquitin-like protein interferon-stimulated gene 15 (ISG15), which is potently induced within the spinal cord following intrathecal delivery of IFNβ. Both free and conjugated ISG15 are elevated following IFNβ treatment, and this effect is increased in UBP43−/− mice lacking a key deconjugating enzyme. The IFNβ-mediated analgesia reduces MAPK signaling activation following nerve injury, and this effect requires induction of ISG15. These findings highlight a new role for IFNβ, ISG15, and MAPK signaling in immunomodulation of neuropathic pain and may lead to new therapeutic possibilities.

      Perspective

      Neuropathic pain is frequently intractable in a clinical setting, and new treatment options are needed. Characterizing the antinociceptive potential of IFNβ and the associated downstream signaling pathways in preclinical models may lead to the development of new therapeutic options for debilitating neuropathies.

      Key words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to The Journal of Pain
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Abraham AK
        • Ramanathan M
        • Weinstock-Guttman B
        • Mager DE
        Mechanisms of interferon-beta effects on bone homeostasis.
        Biochem Pharmacol. 2009; 77: 1757-1762
        • Blalock JE
        • Smith EM
        Human leukocyte interferon: Structural and biological relatedness to adrenocorticotropic hormone and endorphins.
        Proc Natl Acad Sci USA. 1980; 77: 5972-5974
        • Chen Z
        • Doyle TM
        • Luongo L
        • Largent-Milnes TM
        • Giancotti LA
        • Kolar G
        • Squillace S
        • Boccella S
        • Walker JK
        • Pendleton A
        • Spiegel S
        • Neumann WL
        • Vanderah TW
        • Salvemini D
        Sphingosine-1-phosphate receptor 1 activation in astrocytes contributes to neuropathic pain.
        Proc Natl Acad Sci USA. 2019; 116: 10557-10562
        • Cichon J
        • Sun L
        • Yang G
        Spared nerve injury model of neuropathic pain in mice.
        Bio Protoc. 2018; 8: e2777
        • Dafny N
        • Reyes-Vazquez C
        Three different types of alpha-interferons alter naloxone-induced abstinence in morphine-addicted rats.
        Immunopharmacology. 1985; 9: 13-17
        • Dafny N
        • Lee JR
        • Dougherty PM
        Immune response products alter CNS activity: Interferon modulates central opioid functions.
        J Neurosci Res. 1988; 19: 130-139
        • Dafny N
        • Yang PB
        Interferon and the central nervous system.
        Eur J Pharmacol. 2005; 31: 1-15
        • Dao CT
        • Zhang DE
        ISG15: A ubiquitin-like enigma.
        Front Biosci. 2005; 10: 2701-2722
        • Dargahi N
        • Katsara M
        • Tselios T
        • Androutsou ME
        • de Courten M
        • Matsoukas J
        • Apostolopoulos V
        Multiple sclerosis: Immunopathology and treatment update..
        Brain Sci. 2017; 7: e78
        • Darwich L
        • Coma G
        • Peña R
        • Bellido R
        • Blanco EJ
        • Este JA
        • Borras FE
        • Clotet B
        • Ruiz L
        • Rosell A
        • Andreo F
        • Parkhouse RM
        • Bofill M
        Secretion of interferon-gamma by human macrophages demonstrated at the single-cell level after costimulation with interleukin (IL)-12 plus IL-18.
        Immunology. 2009; 126: 386-393
        • D'Cunha J
        • Knight Jr, E
        • Haas AL
        • Truitt RL
        • Borden EC
        Immunoregulatory properties of ISG15, an interferon-induced cytokine.
        Proc Natl Acad Sci USA. 1996; 93: 211-215
        • De Simone R
        • Levi G
        • Aloisi F
        Interferon gamma gene expression in rat central nervous system glial cells.
        Cytokine. 1998; 10: 418-422
        • Decosterd I
        • Woolf CJ
        Spared nerve injury: An animal model of persistent peripheral neuropathic pain.
        Pain. 2000; 87: 149-158
        • Der SD
        • Zhou A
        • Williams BR
        • Silverman RH
        Identification of genes differentially regulated by interferon alpha, beta, or gamma using oligonucleotide arrays.
        Proc Natl Acad Sci USA. 1998; 95: 15623-15628
        • Desai SD
        • Haas AL
        • Wood LM
        • Tsai YC
        • Pestka S
        • Rubin EH
        • Saleem A
        • Nur-E-Kamal A
        • Liu LF
        Elevated expression of ISG15 in tumor cells interferes with the ubiquitin/26S proteasome pathway.
        Cancer Res. 2006; 66: 921-928
        • Dunn AL
        • Crnic LS
        Repeated injections of interferon-alpha A/D in Balb/c mice: Behavioral effects.
        Brain Behav Immun. 1993; 7: 104-111
        • Fillingim RB
        • King CD
        • Ribeiro-Dasilva MC
        • Rahim-Williams B
        • Riley 3rd, JL
        Sex, gender, and pain: A review of recent clinical and experimental findings.
        J Pain. 2009; 10: 447-485
        • Friedman RM
        • Contente S
        Interferons as therapy for viral and neoplastic diseases: From Panacea to Pariah to Paragon.
        Pharmaceuticals (Basel). 2009; 2: 206-216
        • Gargiulo S
        • Greco A
        • Gramanzini M
        • Esposito S
        • Affuso A
        • Brunetti A
        • Vesce G
        Mice anesthesia, analgesia, and care, Part I: Anesthetic considerations in preclinical research.
        ILAR J. 2012; 53: E55-E69
        • Gironi M
        • Martinelli V
        • Brambilla E
        • Furlan R
        • Panerai AE
        • Comi G
        • Sacerdote P
        Beta-endorphin concentrations in peripheral blood mononuclear cells of patients with multiple sclerosis: Effects of treatment with interferon beta.
        Arch Neurol. 2000; 57: 1178-1181
        • Haas AL
        • Ahrens P
        • Bright PM
        • Ankel H
        Interferon induces a 15-kilodalton protein exhibiting marked homology to ubiquitin.
        J Biol Chem. 1987; 262: 11315-11323
        • Havell EA
        • Hayes TG
        • Vilcek J
        Synthesis of two distinct interferons by human fibroblasts.
        Virology. 1978; 89: 330-334
        • Heim MH
        Interferons and hepatitis C virus.
        Swiss Med Wkly. 2012; 142: w13586
        • Heine S
        • Ebnet J
        • Maysami S
        • Stangel M
        Effects of interferon beta on oligodendroglial cells.
        J Neuroimmunol. 2006; 177: 173-180
        • Hori T
        • Katafuchi T
        • Take S
        • Shimizu N
        Neuroimmunomodulatory actions of hypothalamic interferon-alpha.
        Neuroimmunomodulation. 1998; 5: 172-177
        • Jeon YJ
        • Choi JS
        • Lee JY
        • Yu KR
        • Kim SM
        • Ka SH
        • Oh KH
        • Kim KI
        • Zhang DE
        • Bang OS
        • Chung CH
        ISG15 modification of filamin B negatively regulates the type I interferon-induced JNK signalling pathway.
        EMBO Rep. 2009; 10: 374-380
        • Ji RR
        • Gereau 4th, RW
        • Malcangio M
        • Strichartz GR
        MAP kinase and pain.
        Brain Res Rev. 2009; 60: 135-148
        • Jörnvall H
        • Persson M
        • Ekman R
        Structural comparisons of leukocyte interferon and pro-opiomelanocortin correlated with immunological similarities.
        FEBS Lett. 1982; 137: 153-156
        • Kalinke U
        • Prinz M
        Endogenous, or therapeutically induced, type I interferon responses differentially modulate Th1/Th17-mediated autoimmunity in the CNS.
        Immunol Cell Biol. 2012; 90: 505-509
        • Kay NE
        • Morley JE
        • Allen JI
        Interaction between endogenous opioids and IL-2 on PHA-stimulated human lymphocytes.
        Immunology. 1990; 70: 485-491
        • Kim SH
        • Chung JM
        An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat.
        Pain. 1992; 50: 355-363
        • Kobayashi T
        • Washiyama K
        • Ikeda K
        Effects of interferon-alpha on cloned opioid receptors expressed in Xenopus oocytes.
        Life Sci. 2004; 76: 407-415
        • Kraaij MD
        • Vereyken EJ
        • Leenen PJ
        • van den Bosch TP
        • Rezaee F
        • Betjes MG
        • Baan CC
        • Rowshani AT
        Human monocytes produce interferon-gamma upon stimulation with LPS.
        Cytokine. 2014; 67: 7-12
        • Le Page C
        • Génin P
        • Baines MG
        • Hiscott J
        Interferon activation and innate immunity.
        Rev Immunogenet. 2000; 2: 374-386
        • Lee JK
        • Park SH
        • Sim YB
        • Jung JS
        • Suh HW
        Interaction of supraspinally administered interferon-α with opioid system in the production of antinociception.
        Arch Pharm Res. 2010; 33: 1059-1063
        • Liu CC
        • Gao YJ
        • Luo H
        • Berta T
        • Xu ZZ
        • Ji RR
        • Tan PH
        Interferon alpha inhibits spinal cord synaptic and nociceptive transmission via neuronal-glial interactions.
        Sci Rep. 2016; 6: 34356
        • Liu M
        • Li XL
        • Hassel BA
        Proteasomes modulate conjugation to the ubiquitin-like protein, ISG15.
        J Biol Chem. 2003; 278: 1594-1602
        • Malakhov MP
        • Malakhova OA
        • Kim KI
        • Ritchie KJ
        • Zhang DE
        UBP43 (USP18) specifically removes ISG15 from conjugated proteins.
        J Biol Chem. 2002; 277: 9976-9981
        • Martensen PM
        • Justesen J
        Small ISGs coming forward..
        J Interferon Cytokine Res. 2004; 24: 1-19
        • Menzies RA
        • Patel R
        • Hall NR
        • O'Grady MP
        • Rier SE
        Human recombinant interferon alpha inhibits naloxone binding to rat brain membranes.
        Life Sci. 1992; 50: PL227-PL232
        • Moss A
        • Blackburn-Munro G
        • Garry EM
        • Blakemore JA
        • Dickinson T
        • Rosie R
        • Mitchell R
        • Fleetwood-Walker SM
        A role of the ubiquitin-proteasome system in neuropathic pain.
        J Neurosci. 2002; 22: 1363-1372
        • Nakamura M
        • Tanigawa Y
        Ubiquitin-like polypeptide inhibits cAMP-induced p38 MAPK activation in Th2 cells.
        Immunobiology. 2004; 208: 439-444
        • Obata K
        • Noguchi K
        MAPK activation in nociceptive neurons and pain hypersensitivity.
        Life Sci. 2004; 74: 2643-2653
        • Okada K
        • Kuroda E
        • Yoshida Y
        • Yamashita U
        • Suzumura A
        • Tsuji S
        Effects of interferon-beta on the cytokine production of astrocytes.
        J Neuroimmunol. 2005; 159: 48-54
        • Ossipov MH
        • Bazov I
        • Gardell LR
        • Kowal J
        • Yakovleva T
        • Usynin I
        • Ekström TJ
        • Porreca F
        • Bakalkin G
        Control of chronic pain by the ubiquitin proteasome system in the spinal cord.
        J Neurosci. 2007; 27: 8226-8237
        • Pertin M
        • Allchorne AJ
        • Beggah AT
        • Woolf CJ
        • Decosterd I
        Delayed sympathetic dependence in the spared nerve injury (SNI) model of neuropathic pain.
        Mol Pain. 2007; 3: 21
        • Platanias LC
        Mechanisms of type-I- and type-II-interferon-mediated signalling.
        Nat Rev Immunol. 2005; 5: 375-386
        • Plata-Salamán CR
        Interferons and central regulation of feeding.
        Am J Physiol. 1992; 263: R1222-R1227
        • Reyes-Vázquez C
        • Prieto-Gómez B
        • Dafny N
        Alpha-interferon suppresses food intake and neuronal activity of the lateral hypothalamus.
        Neuropharmacology. 1994; 33: 1545-1552
        • Rijckborst V
        • Janssen HL
        The role of interferon in hepatitis B therapy.
        Curr Hepat Rep. 2010; 9: 231-238
        • Ritchie KJ
        • Malakhov MP
        • Hetherington CJ
        • Zhou L
        • Little MT
        • Malakhova OA
        • Sipe JC
        • Orkin SH
        • Zhang DE
        Dysregulation of protein modification by ISG15 results in brain cell injury.
        Genes Dev. 2002; 16: 2207-2212
        • Rosen S
        • Ham B
        • Mogil JS
        Sex differences in neuroimmunity and pain.
        J Neurosci Res. 2017; 95: 500-508
        • Saphier D
        • Welch JE
        • Chuluyan HE
        Alpha-interferon inhibits adrenocortical secretion via mu 1-opioid receptors in the rat.
        Eur J Pharmacol. 1993; 236: 183-191
        • Segall MA
        • Crnic LS
        An animal model for the behavioral effects of interferon.
        Behav Neurosci. 1990; 104: 612-618
        • Shields SD
        • Eckert 3rd, WA
        • Basbaum AI
        Spared nerve injury model of neuropathic pain in the mouse: A behavioral and anatomic analysis.
        J Pain. 2003; 4: 465-470
        • Sorge RE
        • Totsch SK
        Sex differences in pain.
        J Neurosci Res. 2017; 95: 1271-1281
        • Takeuchi T
        • Yokosawa H
        ISG15 modification of Ubc13 suppresses its ubiquitin-conjugating activity.
        Biochem Biophys Res Commun. 2005; 336: 9-13
        • Tan PH
        • Gao YJ
        • Berta T
        • Xu ZZ
        • Ji RR
        Short small-interfering RNAs produce interferon-α-mediated analgesia.
        Br J Anaesth. 2012; 108: 662-669
        • Tsuda M
        • Masuda T
        • Kitano J
        • Shimoyama H
        • Tozaki-Saitoh H
        • Inoue K
        IFN-gamma receptor signaling mediates spinal microglia activation driving neuropathic pain.
        Proc Natl Acad Sci USA. 2009; 106: 8032-8037
        • Vacca V
        • Marinelli S
        • Pieroni L
        • Urbani A
        • Luvisetto S
        • Pavone F
        Higher pain perception and lack of recovery from neuropathic pain in females: A behavioural, immunohistochemical, and proteomic investigation on sex-related differences in mice.
        Pain. 2014; 155: 388-402
        • Valente G
        • Ozmen L
        • Novelli F
        • Geuna M
        • Palestro G
        • Forni G
        • Garotta G
        Distribution of interferon-gamma receptor in human tissues.
        Eur J Immunol. 1992; 22: 2403-2412
        • Vanguri P
        Interferon-gamma-inducible genes in primary glial cells of the central nervous system: Comparisons of astrocytes with microglia and Lewis with brown Norway rats.
        J Neuroimmunol. 1995; 56: 35-43
        • Vikman KS
        • Hill RH
        • Backström E
        • Robertson B
        • Kristensson K
        Interferon-gamma induces characteristics of central sensitization in spinal dorsal horn neurons in vitro.
        Pain. 2003; 106: 241-251
        • Wang BX
        • Rahbar R
        • Fish EN
        Interferon: Current status and future prospects in cancer therapy.
        J Interferon Cytokine Res. 2011; 31: 545-552
        • Yeh ET
        • Gong L
        • Kamitani T
        Ubiquitin-like proteins: New wines in new bottles.
        Gene. 2000; 248: 1-14
        • Zhang D
        • Zhang DE
        Interferon-stimulated gene 15 and the protein ISGylation system.
        J Interferon Cytokine Res. 2011; 31: 119-130
        • Zhang MD
        • Su J
        • Adori C
        • Cinquina V
        • Malenczyk K
        • Girach F
        • Peng C
        • Ernfors P
        • Löw P
        • Borgius L
        • Kiehn O
        • Watanabe M
        • Uhlén M
        • Mitsios N
        • Mulder J
        • Harkany T
        • Hökfelt T
        Ca2+-binding protein NECAB2 facilitates inflammatory pain hypersensitivity.
        J Clin Invest. 2018; 128: 3757-3768