Vol 13, No 2 (2019)
Review paper
Published online: 2019-06-05
Immunology for palliative medicine specialists. The role of Toll-like receptors in inducing disease symptoms
Palliat Med Pract 2019;13(2):57-64.
Abstract
Organizm ludzki ochraniany jest przed czynnikami szkodliwymi pochodzącymi ze świata zewnętrznego i wewnętrznego poprzez system odporności wrodzonej i nabytej, które współpracują ze sobą zarówno u osób zdrowych, jak i u chorych. Receptory Toll-like zlokalizowane są na powierzchni komórek mikrogleju i biorą udział w rozwoju zapalenia neurogennego, które z kolei prowadzi do wystąpienia wielu chorób i objawów, takich jak: depresja, zmęczenie, ból przewlekły i neuropatyczny, kaszel, zaparcie stolca i świąd. Aktywację receptorów Toll-like hamują między innymi leki przeciwdepresyjne. Prawdopodobnie w niedalekiej przyszłości poznane zostaną nowsze leki, skuteczniej hamujące rozwój zapalenia neurogennego, co pozwoli skuteczniej leczyć objawy oporne na standardową farmakoterapię.
Keywords: innate immunityacquired immunitymicrogliaToll-like receptorsPro-nociceptive cytokinesneurogenic inflammation
References
- Gill SR, Pop M, Deboy RT, et al. Metagenomic analysis of the human distal gut microbiome. Science. 2006; 312(5778): 1355–1359.
- Cho I, Blaser MJ. The human microbiome: at the interface of health and disease. Nat Rev Genet. 2012; 13(4): 260–270.
- de Weerth C. Do bacteria shape our development? Crosstalk between intestinal microbiota and HPA axis. Neurosci Biobehav Rev. 2017; 83: 458–471.
- Newburg DS. Neonatal protection by an innate immune system of human milk consisting of oligosaccharides and glycans. J Anim Sci. 2009; 87(13 Suppl): 26–34.
- O'Mahony SM, Clarke G, Borre YE, et al. Serotonin, tryptophan metabolism and the brain-gut-microbiome axis. Behav Brain Res. 2015; 277: 32–48.
- Foster JA, McVey Neufeld KA. Gut-brain axis: how the microbiome influences anxiety and depression. Trends Neurosci. 2013; 36(5): 305–312.
- Sampson TR, Mazmanian SK. Control of brain development, function, and behavior by the microbiome. Cell Host Microbe. 2015; 17(5): 565–576.
- Perry S, de Jong BC, Solnick JV, et al. Infection with Helicobacter pylori is associated with protection against tuberculosis. PLoS One. 2010; 5(1): e8804.
- Higgins PDR, Johnson LA, Luther J, et al. Prior Helicobacter pylori infection ameliorates Salmonella typhimurium-induced colitis: mucosal crosstalk between stomach and distal intestine. Inflamm Bowel Dis. 2011; 17(6): 1398–1408.
- Pedrini MJ, Seewann A, Bennett KA, et al. Helicobacter pylori infection as a protective factor against multiple sclerosis risk in females. J Neurol Neurosurg Psychiatry. 2015; 86(6): 603–607.
- Atherton JC, Blaser MJ. Coadaptation of Helicobacter pylori and humans: ancient history, modern implications. J Clin Invest. 2009; 119(9): 2475–2487.
- Jakobsson HE, Jernberg C, Andersson AF, et al. Short-term antibiotic treatment has differing long-term impacts on the human throat and gut microbiome. PLoS One. 2010; 5(3): e9836.
- Wang F, Meng J, Zhang Li, et al. Morphine induces changes in the gut microbiome and metabolome in a morphine dependence model. Sci Rep. 2018; 8(1): 3596.
- Cook MD, Allen JM, Pence BD, et al. Exercise and gut immune function: evidence of alterations in colon immune cell homeostasis and microbiome characteristics with exercise training. Immunol Cell Biol. 2016; 94(2): 158–163.
- Seidel J, Valenzano DR. The role of the gut microbiome during host ageing. F1000Res. 2018; 7.
- Moresco EM, LaVine D, Beutler B. Toll-like receptors. Curr Biol. 2011; 21(13): R488–R493.
- Harrison NA, Brydon L, Walker C, et al. Neural origins of human sickness in interoceptive responses to inflammation. Biol Psychiatry. 2009; 66(5): 415–422.
- Higgins SC, Lavelle EdC, McCann C, et al. Toll-like receptor 4-mediated innate IL-10 activates antigen-specific regulatory T cells and confers resistance to Bordetella pertussis by inhibiting inflammatory pathology. J Immunol. 2003; 171(6): 3119–3127.
- Wachholz S, Eßlinger M, Plümper J, et al. Microglia activation is associated with IFN-α induced depressive-like behavior. Brain Behav Immun. 2016; 55: 105–113.
- Pandey GN, Rizavi HS, Bhaumik R, et al. Toll-like receptors in the depressed and suicide brain. J Psychiatr Res. 2014; 53: 62–68.
- Sanchez-Guajardo V, Tentillier N, Romero-Ramos M. The relation between α-synuclein and microglia in Parkinson's disease: Recent developments. Neuroscience. 2015; 302: 47–58.
- Fuxe KG, Tarakanov AO, Goncharova LB, et al. A new road to neuroinflammation in Parkinson's disease? Brain Res Rev. 2008; 58(2): 453–458.
- Doorn KJ, Moors T, Drukarch B, et al. Microglial phenotypes and toll-like receptor 2 in the substantia nigra and hippocampus of incidental Lewy body disease cases and Parkinson's disease patients. Acta Neuropathol Commun. 2014; 2: 90.
- Nyati KK, Prasad KN. Role of cytokines and Toll-like receptors in the immunopathogenesis of Guillain-Barré syndrome. Mediators Inflamm. 2014; 2014: 758639.
- Gooshe M, Abdolghaffari AH, Gambuzza ME, et al. The role of Toll-like receptors in multiple sclerosis and possible targeting for therapeutic purposes. Rev Neurosci. 2014; 25(5): 713–739.
- Husseinzadeh N, Davenport SM. Role of toll-like receptors in cervical, endometrial and ovarian cancers: a review. Gynecol Oncol. 2014; 135(2): 359–363.
- Moossavi S, Rezaei N. Toll-like receptor signalling and their therapeutic targeting in colorectal cancer. Int Immunopharmacol. 2013; 16(2): 199–209.
- Xu Y, Liu H, Liu S, et al. Genetic variant of IRAK2 in the toll-like receptor signaling pathway and survival of non-small cell lung cancer. Int J Cancer. 2018; 143(10): 2400–2408.
- Song IJ, Yang YM, Inokuchi-Shimizu S, et al. The contribution of toll-like receptor signaling to the development of liver fibrosis and cancer in hepatocyte-specific TAK1-deleted mice. Int J Cancer. 2018; 142(1): 81–91.
- Young JJ, Bruno D, Pomara N. A review of the relationship between proinflammatory cytokines and major depressive disorder. J Affect Disord. 2014; 169: 15–20.
- Raison CL, Capuron L, Miller AH. Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends Immunol. 2006; 27(1): 24–31.
- Alesci S, Martinez PE, Kelkar S, et al. Major depression is associated with significant diurnal elevations in plasma interleukin-6 levels, a shift of its circadian rhythm, and loss of physiological complexity in its secretion: clinical implications. J Clin Endocrinol Metab. 2005; 90(5): 2522–2530.
- Miller GE, Stetler CA, Carney RM, et al. Clinical depression and inflammatory risk markers for coronary heart disease. Am J Cardiol. 2002; 90(12): 1279–1283.
- Thomas AJ, Davis S, Morris C, et al. Increase in interleukin-1beta in late-life depression. Am J Psychiatry. 2005; 162(1): 175–177.
- Capuron L, Miller AH. Cytokines and psychopathology: lessons from interferon-alpha. Biol Psychiatry. 2004; 56(11): 819–824.
- Musselman DL, Lawson DH, Gumnick JF, et al. Paroxetine for the prevention of depression induced by high-dose interferon alfa. N Engl J Med. 2001; 344(13): 961–966.
- Capuron L, Ravaud A, Neveu PJ, et al. Association between decreased serum tryptophan concentrations and depressive symptoms in cancer patients undergoing cytokine therapy. Mol Psychiatry. 2002; 7(5): 468–473.
- Dahl J, Ormstad H, Aass HC, et al. The plasma levels of various cytokines are increased during ongoing depression and are reduced to normal levels after recovery. Psychoneuroendocrinology. 2014; 45: 77–86.
- Chen CY, Yeh YW, Kuo SC, et al. Differences in immunomodulatory properties between venlafaxine and paroxetine in patients with major depressive disorder. Psychoneuroendocrinology. 2018; 87: 108–118.
- Halaris A, Myint AM, Savant V, et al. Does escitalopram reduce neurotoxicity in major depression? J Psychiatr Res. 2015; 66-67: 118–126.
- Durairaj H, Steury MD, Parameswaran N. Paroxetine differentially modulates LPS-induced TNFα and IL-6 production in mouse macrophages. Int Immunopharmacol. 2015; 25(2): 485–492.
- Grace PM, Rolan PE, Hutchinson MR. Peripheral immune contributions to the maintenance of central glial activation underlying neuropathic pain. Brain Behav Immun. 2011; 25(7): 1322–1332.
- Milligan ED, Watkins LR. Pathological and protective roles of glia in chronic pain. Nat Rev Neurosci. 2009; 10(1): 23–36.
- Hutchinson MR, Shavit Y, Grace PM, et al. Exploring the neuroimmunopharmacology of opioids: an integrative review of mechanisms of central immune signaling and their implications for opioid analgesia. Pharmacol Rev. 2011; 63(3): 772–810.
- Hutchinson MR, Zhang Y, Shridhar M, et al. Evidence that opioids may have toll-like receptor 4 and MD-2 effects. Brain Behav Immun. 2010; 24(1): 83–95.
- Eidson LN, Murphy AZ. Blockade of Toll-like receptor 4 attenuates morphine tolerance and facilitates the pain relieving properties of morphine. J Neurosci. 2013; 33(40): 15952–15963.
- Hutchinson MR, Loram LC, Zhang Y, et al. Evidence that tricyclic small molecules may possess toll-like receptor and myeloid differentiation protein 2 activity. Neuroscience. 2010; 168(2): 551–563.
- Raynor K, Kong H, Chen Y, et al. Pharmacological characterization of the cloned kappa-, delta-, and mu-opioid receptors. Mol Pharmacol. 1994; 45(2): 330–334.
- Wang X, Zhang Y, Peng Y, et al. Pharmacological characterization of the opioid inactive isomers (+)-naltrexone and (+)-naloxone as antagonists of toll-like receptor 4. Br J Pharmacol. 2016; 173(5): 856–869.
- Cheng W, Li Y, Hou X, et al. HSP60 is involved in the neuroprotective effects of naloxone. Mol Med Rep. 2014; 10(4): 2172–2176.
- Hutchinson MR, Northcutt AL, Hiranita T, et al. Opioid activation of toll-like receptor 4 contributes to drug reinforcement. J Neurosci. 2012; 32(33): 11187–11200.
- Lewis SS, Loram LC, Hutchinson MR, et al. (+)-naloxone, an opioid-inactive toll-like receptor 4 signaling inhibitor, reverses multiple models of chronic neuropathic pain in rats. J Pain. 2012; 13(5): 498–506.
- Mika J. Modulation of microglia can attenuate neuropathic pain symptoms and enhance morphine effectiveness. Pharmacol Rep. 2008; 60(3): 297–307.
- Jurga AM, Rojewska E, Piotrowska A, et al. Blockade of Toll-Like Receptors (TLR2, TLR4) Attenuates Pain and Potentiates Buprenorphine Analgesia in a Rat Neuropathic Pain Model. Neural Plast. 2016; 2016: 5238730.
- Yu HR, Huang HC, Kuo HC, et al. IFN-α production by human mononuclear cells infected with varicella-zoster virus through TLR9-dependent and -independent pathways. Cell Mol Immunol. 2011; 8(2): 181–188.
- Liu T, Gao YJ, Ji RR. Emerging role of Toll-like receptors in the control of pain and itch. Neurosci Bull. 2012; 28(2): 131–144.
- Due MR, Piekarz AD, Wilson N, et al. Neuroexcitatory effects of morphine-3-glucuronide are dependent on Toll-like receptor 4 signaling. J Neuroinflammation. 2012; 9: 200.
- Lewis SS, Hutchinson MR, Rezvani N, et al. Evidence that intrathecal morphine-3-glucuronide may cause pain enhancement via toll-like receptor 4/MD-2 and interleukin-1beta. Neuroscience. 2010; 165(2): 569–583.
- Lewis SS, Hutchinson MR, Rezvani N, et al. Evidence that intrathecal morphine-3-glucuronide may cause pain enhancement via toll-like receptor 4/MD-2 and interleukin-1beta. Neuroscience. 2010; 165(2): 569–583.
- Lewis SS, Hutchinson MR, Frick MM, et al. Select steroid hormone glucuronide metabolites can cause toll-like receptor 4 activation and enhanced pain. Brain Behav Immun. 2015; 44: 128–136.
- Jin XH, Wang LN, Zuo JL, et al. P2X4 receptor in the dorsal horn partially contributes to brain-derived neurotrophic factor oversecretion and toll-like receptor-4 receptor activation associated with bone cancer pain. J Neurosci Res. 2014; 92(12): 1690–1702.
- Nagata K, Imai T, Yamashita T, et al. Antidepressants inhibit P2X4 receptor function: a possible involvement in neuropathic pain relief. Mol Pain. 2009; 5: 20.
- Sobczak M, Sałaga M, Storr MA, et al. Physiology, signaling, and pharmacology of opioid receptors and their ligands in the gastrointestinal tract: current concepts and future perspectives. J Gastroenterol. 2014; 49(1): 24–45.
- Lay J, Carbone SE, DiCello JJ, et al. Distribution and trafficking of the μ-opioid receptor in enteric neurons of the guinea pig. Am J Physiol Gastrointest Liver Physiol. 2016; 311(2): G252–G266.
- Farzi A, Halicka J, Mayerhofer R, et al. Toll-like receptor 4 contributes to the inhibitory effect of morphine on colonic motility in vitro and in vivo. Sci Rep. 2015; 5: 9499.
- Ishihara S, Tada Y, Fukuba N, et al. Pathogenesis of irritable bowel syndrome--review regarding associated infection and immune activation. Digestion. 2013; 87(3): 204–211.
- Meissner W, Schmidt U, Hartmann M, et al. Oral naloxone reverses opioid-associated constipation. Pain. 2000; 84(1): 105–109.
- Meissner W, Leyendecker P, Mueller-Lissner S, et al. A randomised controlled trial with prolonged-release oral oxycodone and naloxone to prevent and reverse opioid-induced constipation. Eur J Pain. 2009; 13(1): 56–64.
- Ur E, White PD, Grossman A. Hypothesis: cytokines may be activated to cause depressive illness and chronic fatigue syndrome. Eur Arch Psychiatry Clin Neurosci. 1992; 241(5): 317–322.
- Lucas K, Morris G, Anderson G, et al. The Toll-Like Receptor Radical Cycle Pathway: A New Drug Target in Immune-Related Chronic Fatigue. CNS Neurol Disord Drug Targets. 2015; 14(7): 838–854.
- Twycross R, Greaves MW, Handwerker H, et al. Itch: scratching more than the surface. QJM. 2003; 96(1): 7–26.
- Ji RR. Neuroimmune interactions in itch: Do chronic itch, chronic pain, and chronic cough share similar mechanisms? Pulm Pharmacol Ther. 2015; 35: 81–86.
- Taves S, Ji RR. Itch control by Toll-like receptors. Handb Exp Pharmacol. 2015; 226: 135–150.
- Liu T, Xu ZZ, Park CK, et al. Toll-like receptor 7 mediates pruritus. Nat Neurosci. 2010; 13(12): 1460–1462.
- Belghiti M, Estévez-Herrera J, Giménez-Garzó C, et al. Potentiation of the transient receptor potential vanilloid 1 channel contributes to pruritogenesis in a rat model of liver disease. J Biol Chem. 2013; 288(14): 9675–9685.
- Nattkemper LA, Martinez-Escala ME, Gelman AB, et al. Cutaneous T-cell Lymphoma and Pruritus: The Expression of IL-31 and its Receptors in the Skin. Acta Derm Venereol. 2016; 96(7): 894–898.
- Takamori A, Nambu A, Sato K, et al. IL-31 is crucial for induction of pruritus, but not inflammation, in contact hypersensitivity. Sci Rep. 2018; 8(1): 6639.
- Tsuda M, Masuda T, Tozaki-Saitoh H, et al. P2X4 receptors and neuropathic pain. Front Cell Neurosci. 2013; 7: 191.
- Trang T, Salter MW. P2X4 purinoceptor signaling in chronic pain. Purinergic Signal. 2012; 8(3): 621–628.
- Zylicz Z, Krajnik M, Sorge AA, et al. Paroxetine in the treatment of severe non-dermatological pruritus: a randomized, controlled trial. J Pain Symptom Manage. 2003; 26(6): 1105–1112.
- Mayo MJ, Handem I, Saldana S, et al. Sertraline as a first-line treatment for cholestatic pruritus. Hepatology. 2007; 45(3): 666–674.
- Ständer S, Böckenholt B, Schürmeyer-Horst F, et al. Treatment of chronic pruritus with the selective serotonin re-uptake inhibitors paroxetine and fluvoxamine: results of an open-labelled, two-arm proof-of-concept study. Acta Derm Venereol. 2009; 89(1): 45–51.
- Tynan RJ, Weidenhofer J, Hinwood M, et al. A comparative examination of the anti-inflammatory effects of SSRI and SNRI antidepressants on LPS stimulated microglia. Brain Behav Immun. 2012; 26(3): 469–479.
- Chung KF, McGarvey L, Mazzone SB. Chronic cough as a neuropathic disorder. Lancet Respir Med. 2013; 1(5): 414–422.
- Haran JP, Buglione-Corbett R, Lu S. Cytokine markers as predictors of type of respiratory infection in patients during the influenza season. Am J Emerg Med. 2013; 31(5): 816–821.
- Nemes E, Rozot V, Geldenhuys H, et al. C-040-404 Study Team and the Adolescent Cohort Study Team. Optimization and Interpretation of Serial QuantiFERON Testing to Measure Acquisition of Mycobacterium tuberculosis Infection. Am J Respir Crit Care Med. 2017; 196(5): 638–648.
- Tsuda M, Masuda T, Kitano J, et al. IFN-gamma receptor signaling mediates spinal microglia activation driving neuropathic pain. Proc Natl Acad Sci U S A. 2009; 106(19): 8032–8037.
- Blaszczyk F. Oronska, A., Krajnik, M., Zylicz, Z. Fluvoxamine efficacy in severe dry cough in neoplasmatic disease. Polska Medycyna Paliatywna. 2005; 4: 17–20.
- Zylicz Z, Krajnik M. What has dry cough in common with pruritus? Treatment of dry cough with paroxetine. J Pain Symptom Manage. 2004; 27(2): 180–184.
- Amini S, Peiman S, Khatuni M, et al. The Effect of Dextromethorphan Premedication on Cough and Patient Tolerance During Flexible Bronchoscopy: A Randomized, Double-blind, Placebo-controlled Trial. J Bronchology Interv Pulmonol. 2017; 24(4): 263–267.
- Haase J, Brown E. Integrating the monoamine, neurotrophin and cytokine hypotheses of depression--a central role for the serotonin transporter? Pharmacol Ther. 2015; 147: 1–11.
- Lee YC, Chen PP. A review of SSRIs and SNRIs in neuropathic pain. Expert Opin Pharmacother. 2010; 11(17): 2813–2825.
- Hegade VS, Bolier R, Oude Elferink RPj, et al. Advances in pathogenesis and treatment of pruritus. Clin Liver Dis. 2013; 17(2): 319–329.
- Kaul I, Amin A, Rosenberg M, et al. Use of gabapentin and pregabalin for pruritus and neuropathic pain associated with major burn injury: A retrospective chart review. Burns. 2018; 44(2): 414–422.
- Zylicz Z. Krajnik, M., . The effect of gabapentin and pregabalin on symptoms other than pain and seizures. A review of the evidence. Adv Pall Med. 2008; 4: 179–84.
- Coplan PM, Sessler NE, Harikrishnan V, et al. Comparison of abuse, suspected suicidal intent, and fatalities related to the 7-day buprenorphine transdermal patch versus other opioid analgesics in the National Poison Data System. Postgrad Med. 2017; 129(1): 55–61.
- Leon AC, Marzuk PM, Tardiff K, et al. Paroxetine, other antidepressants, and youth suicide in New York City: 1993 through 1998. J Clin Psychiatry. 2004; 65(7): 915–918.
