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In vivo and systems biology studies implicate IL-18 as a central mediator in chronic pain

      Highlights

      • Multiplex cytokine protein expression in rat CCI sciatic nerve was studied.
      • Immunohistology of the CCI sciatic nerve confirms inflammasome activation.
      • Dynamic Bayesian Network inference identified interleukin (IL)-18 as a central node.
      • DBN shows interactions among IFN-γ, IL-1β and IL-18 contribute to neuropathic pain.
      • In vivo/in silico approach provides unique insight into chronic neuropathic pain.

      Abstract

      Inflammation is associated with peripheral neuropathy, however the interplay among cytokines, chemokines, and neurons is still unclear. We hypothesized that this neuroinflammatory interaction can be defined by computational modeling based on the dynamics of protein expression in the sciatic nerve of rats subjected to chronic constriction injury. Using Dynamic Bayesian Network inference, we identified interleukin (IL)-18 as a central node associated with neuropathic pain in this animal model. Immunofluorescence supported a role for inflammasome activation and induction of IL-18 at the site of injury. Combined in vivo and in silico approaches may thus highlight novel targets in peripheral neuropathy.

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      References

        • Abbadie C.
        • Bhangoo S.
        • De Koninck Y.
        • Malcangio M.
        • Melik-Parsadaniantz S.
        • White F.A.
        Chemokines and pain mechanisms.
        Brain Res. Rev. 2009; 60: 125-134
        • Aderhold A.
        • Husmeier D.
        • Grzegorczyk M.
        Statistical inference of regulatory networks for circadian regulation.
        Stat. Appl. Genet. Mol. Biol. 2014; 13: 227-273
        • Aerts J.M.
        • Haddad W.M.
        • An G.
        • Vodovotz Y.
        From data patterns to mechanistic models in acute critical illness.
        J. Crit. Care. 2014; 29: 604-610
        • Austin P.J.
        • Moalem-Taylor G.
        The neuro-immune balance in neuropathic pain: involvement of inflammatory immune cells, immune-like glial cells and cytokines.
        J. Neuroimmunol. 2010; 229: 26-50
        • Azhar N.
        • Ziraldo C.
        • Barclay D.
        • Rudnick D.A.
        • Squires R.H.
        • Vodovotz Y.
        • et al.
        Analysis of serum inflammatory mediators identifies unique dynamic networks associated with death and spontaneous survival in pediatric acute liver failure.
        PLoS One. 2013; 8: e78202
        • Baron R.
        • Binder A.
        • Wasner G.
        Neuropathic pain: diagnosis, pathophysiological mechanisms, and treatment.
        Lancet Neurol. 2010; 9: 807-819
        • Barrette B.
        • Hebert M.A.
        • Filali M.
        • Lafortune K.
        • Vallieres N.
        • Gowing G.
        • et al.
        Requirement of myeloid cells for axon regeneration.
        J. Neurosci. 2008; 28: 9363-9376
        • Bennett G.J.
        • Xie Y.K.
        A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man.
        Pain. 1988; 33: 87-107
        • Chen Y.
        • Devor M.
        Ectopic mechanosensitivity in injured sensory axons arises from the site of spontaneous electrogenesis.
        Eur. J. Pain. 1998; 2: 165-178
        • Clark A.K.
        • Old E.A.
        • Malcangio M.
        Neuropathic pain and cytokines: current perspectives.
        J. Pain Res. 2013; 6: 803-814
        • Costigan M.
        • Scholz J.
        • Woolf C.J.
        Neuropathic pain: a maladaptive response of the nervous system to damage.
        Annu. Rev. Neurosci. 2009; 32: 1-32
        • Cui J.G.
        • Holmin S.
        • Mathiesen T.
        • Meyerson B.A.
        • Linderoth B.
        Possible role of inflammatory mediators in tactile hypersensitivity in rat models of mononeuropathy.
        Pain. 2000; 88: 239-248
        • Dinarello C.A.
        • Novick D.
        • Puren A.J.
        • Fantuzzi G.
        • Shapiro L.
        • Muhl H.
        • et al.
        Overview of interleukin-18: more than an interferon-gamma inducing factor.
        J. Leukoc. Biol. 1998; 63: 658-664
        • Dubovy P.
        Wallerian degeneration and peripheral nerve conditions for both axonal regeneration and neuropathic pain induction.
        Ann. Anat. 2011; 193: 267-275
        • Dubovy P.
        • Klusakova I.
        • Hradilova Svizenska I.
        Inflammatory profiling of Schwann cells in contact with growing axons distal to nerve injury.
        BioMed Res. Int. 2014; 2014: 691041
        • Emr B.
        • Sadowsky D.
        • Azhar N.
        • Gatto L.A.
        • An G.
        • Nieman G.F.
        • et al.
        Removal of inflammatory ascites is associated with dynamic modification of local and systemic inflammation along with prevention of acute lung injury: in vivo and in silico studies.
        Shock. 2014; 41: 317-323
        • Fiebich B.L.
        • Mueksch B.
        • Boehringer M.
        • Hull M.
        Interleukin-1beta induces cyclooxygenase-2 and prostaglandin E(2) synthesis in human neuroblastoma cells: involvement of p38 mitogen-activated protein kinase and nuclear factor-kappaB.
        J. Neurochem. 2000; 75: 2020-2028
        • Franchi L.
        • Eigenbrod T.
        • Munoz-Planillo R.
        • Nunez G.
        The inflammasome: a caspase-1-activation platform that regulates immune responses and disease pathogenesis.
        Nat. Immunol. 2009; 10: 241-247
        • Fu S.Y.
        • Gordon T.
        The cellular and molecular basis of peripheral nerve regeneration.
        Mol. Neurobiol. 1997; 14: 67-116
        • Futani H.
        • Okayama A.
        • Matsui K.
        • Kashiwamura S.
        • Sasaki T.
        • Hada T.
        • et al.
        Relation between interleukin-18 and PGE2 in synovial fluid of osteoarthritis: a potential therapeutic target of cartilage degradation.
        J. Immunother. 2002; 25: S61-S64
        • Gaudet A.D.
        • Popovich P.G.
        • Ramer M.S.
        Wallerian degeneration: gaining perspective on inflammatory events after peripheral nerve injury.
        J. Neuroinflammation. 2011; 8: 110
        • Grzegorczyk M.
        • Husmeier D.
        Improvements in the reconstruction of time-varying gene regulatory networks: dynamic programming and regularization by information sharing among genes.
        Bioinformatics. 2011; 27: 693-699
        • Han R.
        • Tsui S.
        • Smith T.J.
        Up-regulation of prostaglandin E2 synthesis by interleukin-1beta in human orbital fibroblasts involves coordinate induction of prostaglandin-endoperoxide H synthase-2 and glutathione-dependent prostaglandin E2 synthase expression.
        J. Biol. Chem. 2002; 277: 16355-16364
        • Hao S.
        • Mata M.
        • Glorioso J.C.
        • Fink D.J.
        HSV-mediated expression of interleukin-4 in dorsal root ganglion neurons reduces neuropathic pain.
        Mol. Pain. 2006; 2: 6
        • IASP
        International association for the study of pain.
        Pain. 2003; XI: 1-4
        • IOM
        Institute of Medicine, Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research.
        The National Academies Press, Washington, DC2011
        • Jensen T.S.
        • Baron R.
        • Haanpaa M.
        • Kalso E.
        • Loeser J.D.
        • Rice A.S.
        • et al.
        A new definition of neuropathic pain.
        Pain. 2011; 152: 2204-2205
        • Ji R.R.
        • Xu Z.Z.
        • Gao Y.J.
        Emerging targets in neuroinflammation-driven chronic pain.
        Nat. Rev. Drug Discov. 2014; 13: 533-548
        • Kajander K.C.
        • Wakisaka S.
        • Bennett G.J.
        Spontaneous discharge originates in the dorsal root ganglion at the onset of a painful peripheral neuropathy in the rat.
        Neurosci. Lett. 1992; 138: 225-228
        • Kashiwamura S.
        • Ueda H.
        • Okamura H.
        Roles of interleukin-18 in tissue destruction and compensatory reactions.
        J. Immunother. 2002; 25: S4-S11
        • Kiguchi N.
        • Kobayashi Y.
        • Kishioka S.
        Chemokines and cytokines in neuroinflammation leading to neuropathic pain.
        Curr. Opin. Pharmacol. 2012; 12: 55-61
        • Kleinschnitz C.
        • Brinkhoff J.
        • Zelenka M.
        • Sommer C.
        • Stoll G.
        The extent of cytokine induction in peripheral nerve lesions depends on the mode of injury and NMDA receptor signaling.
        J. Neuroimmunol. 2004; 149: 77-83
        • Lechtenberg B.C.
        • Mace P.D.
        • Riedl S.J.
        Structural mechanisms in NLR inflammasome signaling.
        Curr. Opin. Struct. Biol. 2014; 29C: 17-25
        • Li W.W.
        • Guo T.Z.
        • Liang D.
        • Shi X.
        • Wei T.
        • Kingery W.S.
        • et al.
        The NALP1 inflammasome controls cytokine production and nociception in a rat fracture model of complex regional pain syndrome.
        Pain. 2009; 147: 277-286
        • Li Q.
        • Tian Y.
        • Wang Z.F.
        • Liu S.B.
        • Mi W.L.
        • Ma H.J.
        • et al.
        Involvement of the spinal NALP1 inflammasome in neuropathic pain and aspirin-triggered-15-epi-lipoxin A4 induced analgesia.
        Neuroscience. 2013; 254: 230-240
        • Ma W.
        • Eisenach J.C.
        Cyclooxygenase 2 in infiltrating inflammatory cells in injured nerve is universally up-regulated following various types of peripheral nerve injury.
        Neuroscience. 2003; 121: 691-704
        • Mi Q.
        • Constantine G.
        • Ziraldo C.
        • Solovyev A.
        • Torres A.
        • Namas R.
        • et al.
        A dynamic view of trauma/hemorrhage-induced inflammation in mice: principal drivers and networks.
        PLoS One. 2011; 6: e19424
        • Moalem G.
        • Xu K.
        • Yu L.
        T lymphocytes play a role in neuropathic pain following peripheral nerve injury in rats.
        Neuroscience. 2004; 129: 767-777
        • Monk K.R.
        • Wu J.
        • Williams J.P.
        • Finney B.A.
        • Fitzgerald M.E.
        • Filippi M.D.
        • et al.
        Mast cells can contribute to axon-glial dissociation and fibrosis in peripheral nerve.
        Neuron Glia Biol. 2007; 3: 233-244
        • Munder M.
        • Mallo M.
        • Eichmann K.
        • Modolell M.
        Murine macrophages secrete interferon gamma upon combined stimulation with interleukin (IL)-12 and IL-18: a novel pathway of autocrine macrophage activation.
        J. Exp. Med. 1998; 187: 2103-2108
        • Nadeau S.
        • Filali M.
        • Zhang J.
        • Kerr B.J.
        • Rivest S.
        • Soulet D.
        • et al.
        Functional recovery after peripheral nerve injury is dependent on the pro-inflammatory cytokines IL-1beta and TNF: implications for neuropathic pain.
        J. Neurosci. 2011; 31: 12533-12542
        • Niemi J.P.
        • DeFrancesco-Lisowitz A.
        • Roldan-Hernandez L.
        • Lindborg J.A.
        • Mandell D.
        • Zigmond R.E.
        A critical role for macrophages near axotomized neuronal cell bodies in stimulating nerve regeneration.
        J. Neurosci. 2013; 33: 16236-16248
        • Okamoto K.
        • Martin D.P.
        • Schmelzer J.D.
        • Mitsui Y.
        • Low P.A.
        Pro- and anti-inflammatory cytokine gene expression in rat sciatic nerve chronic constriction injury model of neuropathic pain.
        Exp. Neurol. 2001; 169: 386-391
        • Olee T.
        • Hashimoto S.
        • Quach J.
        • Lotz M.
        IL-18 is produced by articular chondrocytes and induces proinflammatory and catabolic responses.
        J. Immunol. 1999; 162: 1096-1100
        • Ramesh G.
        • MacLean A.G.
        • Philipp M.T.
        Cytokines and chemokines at the crossroads of neuroinflammation, neurodegeneration, and neuropathic pain.
        Mediat. Inflamm. 2013; 2013: 480739
        • Ren K.
        • Dubner R.
        Interactions between the immune and nervous systems in pain.
        Nat. Med. 2010; 16: 1267-1276
        • Rittner H.L.
        • Machelska H.
        • Stein C.
        Leukocytes in the regulation of pain and analgesia.
        J. Leukoc. Biol. 2005; 78: 1215-1222
        • Sacerdote P.
        • Franchi S.
        • Moretti S.
        • Castelli M.
        • Procacci P.
        • Magnaghi V.
        • et al.
        Cytokine modulation is necessary for efficacious treatment of experimental neuropathic pain.
        J. Neuroimmune Pharmacol. 2013; 8: 202-211
        • Schindler H.
        • Lutz M.B.
        • Rollinghoff M.
        • Bogdan C.
        The production of IFN-gamma by IL-12/IL-18-activated macrophages requires STAT4 signaling and is inhibited by IL-4.
        J. Immunol. 2001; 166: 3075-3082
        • Scholz J.
        • Woolf C.J.
        The neuropathic pain triad: neurons, immune cells and glia.
        Nat. Neurosci. 2007; 10: 1361-1368
        • Schroder K.
        • Tschopp J.
        The inflammasomes.
        Cell. 2010; 140: 821-832
        • Tal M.
        • Eliav E.
        Abnormal discharge originates at the site of nerve injury in experimental constriction neuropathy (CCI) in the rat.
        Pain. 1996; 64: 511-518
        • Tominaga K.
        • Yoshimoto T.
        • Torigoe K.
        • Kurimoto M.
        • Matsui K.
        • Hada T.
        • et al.
        IL-12 synergizes with IL-18 or IL-1beta for IFN-gamma production from human T cells.
        Int. Immunol. 2000; 12: 151-160
        • Vasudeva K.
        • Andersen K.
        • Zeyzus-Johns B.
        • Hitchens T.K.
        • Patel S.K.
        • Balducci A.
        • et al.
        Imaging neuroinflammation in vivo in a neuropathic pain rat model with near-infrared fluorescence and (19)f magnetic resonance.
        PLoS One. 2014; 9: e90589
        • Vodovotz Y.
        Deciphering the complexity of acute inflammation using mathematical models.
        Immunol. Res. 2006; 36: 237-245
        • Vodovotz Y.
        • Billiar T.R.
        In silico modeling: methods and applications to trauma and sepsis.
        Crit. Care Med. 2013; 41: 2008-2014
        • Wang S.
        • Lei T.
        • Zhang K.
        • Zhao W.
        • Fang L.
        • Lai B.
        • et al.
        Xenobiotic receptor PXR regulates innate immunity via activation of NLRP3 inflammasome in vascular endothelial cells.
        J. Biol. Chem. 2004; 289: 30075-30081
        • White F.A.
        • Bhangoo S.K.
        • Miller R.J.
        Chemokines: integrators of pain and inflammation.
        Nat. Rev. Drug Discov. 2005; 4: 834-844
        • Yoshimoto T.
        • Takeda K.
        • Tanaka T.
        • Ohkusu K.
        • Kashiwamura S.
        • Okamura H.
        • et al.
        IL-12 up-regulates IL-18 receptor expression on T cells, Th1 cells, and B cells: synergism with IL-18 for IFN-gamma production.
        J. Immunol. 1998; 161: 3400-3407
        • Zaaqoq A.M.
        • Namas R.
        • Almahmoud K.
        • Azhar N.
        • Mi Q.
        • Zamora R.
        • et al.
        Inducible protein-10, a potential driver of neurally controlled interleukin-10 and morbidity in human blunt trauma.
        Crit. Care Med. 2014; 42: 1487-1497
        • Zhang Y.K.
        • Huang Z.J.
        • Liu S.
        • Liu Y.P.
        • Song A.A.
        • Song X.J.
        WNT signaling underlies the pathogenesis of neuropathic pain in rodents.
        J. Clin. Investig. 2013; 123: 2268-2286