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Anti-inflammatory properties of Liposome-encapsulated clodronate or Anti-Ly6G can be modulated by peripheral or central inflammatory markers in carrageenan-induced inflammation model

  • Tufan MertEmail author
  • Mehmet Sahin
  • Emel Sahin
  • Selma Yaman
Original Article
  • 27 Downloads

Abstract

Overproduction of inflammatory markers by immune cells, such as macrophages and neutrophils, is one of the main reasons for many inflammatory conditions and inhibiting or suppressing of their production by cell depletion may provide new therapeutic targets or approaches to prevent a variety of inflammatory conditions. In this study, we examined the possible effects of anti-Ly6G-mediated systemic neutrophil depletion and liposome-encapsulated clodronate (LEC)-mediated systemic macrophage depletion on the inflammatory signs (thermal hyperalgesia, mechanical allodynia, oedema and fever) and measured the levels of various inflammation markers (tumour necrosis factor-α (TNF-α), interleukins (IL)-1β, IL-4, IL-10, macrophage inflammatory protein-1 alpha (MIP-1α/CCL3) and myeloperoxidase (MPO) in paw and spinal cord tissues in carrageenan (CG)-induced hindpaw inflammation model in rats. CG injection into the paw caused inflammation characterized by redness, swelling, heat and pain hypersensitivities. Anti-Ly6G or LEC significantly ameliorated the pain behaviours, and decreased the oedema and fever. Efficacies of anti-Ly6G or LEC on inflammatory responses changed depend on the degree of inhibition in inflammatory markers of inflamed paw or spinal cord. Anti-inflammatory properties of anti-Ly6G or LEC suggest that macrophages and/or neutrophil-mediated inflammatory cascade in inflamed site and spinal cord which can play key roles in inflammatory pain responses. These systemic or peripheral inflammatory mediators may be therapeutic targets in the treatment of many inflammatory conditions and related various diseases.

Keywords

Inflammation Clodronate Ly6g Cytokine Rat 

Notes

Acknowledgements

This study was financially supported by Grant no. 116S502 from The Scientific and Technological Research Council of Turkey.

Compliance with ethical standards

Conflict of interest

The authors declare that there are no conflicts of interest.

References

  1. Aratani Y (2018) Myeloperoxidase: its role for host defense, inflammation, and neutrophil function. Arch Biochem Biophys 640:47–52CrossRefGoogle Scholar
  2. Basbaum AI, Bautista DM, Scherrer G, Julius D (2009) Cellular and molecular mechanisms of pain. Cell 139:267–284CrossRefGoogle Scholar
  3. Bruhn KW, Dekitani K, Nielsen TB, Pantapalangkoor P, Spellberg B (2015) Ly6G-mediated depletion of neutrophils is dependent on macrophages. Results Immunol 6:5–7CrossRefGoogle Scholar
  4. Bucher K, Schmitt F, Autenrieth SE, Dillmann I, Nürnberg B, Schenke- Layland K, Beer-Hammer S (2015) Fluorescent Ly6G antibodies determine macrophage phagocytosis of neutrophils and alter the retrieval of neutrophils in mice. J Leukoc Biol 98:365–372CrossRefGoogle Scholar
  5. Dawes JM, McMahon SB (2013) Chemokines as peripheral pain mediators. Neurosci Lett 557:1–8CrossRefGoogle Scholar
  6. Dawes JM, Vincent A (2016) Autoantibodies and pain. Curr Opin Support Palliat Care 10:137–142CrossRefGoogle Scholar
  7. Duque GA, Descoteaux A (2014) Macrophage cytokines: involvement in immunity and infectious diseases. Front Immunol 5:491Google Scholar
  8. Fox S, Leitch AE, Duffin R, Haslett C, Rossi AG (2010) Neutrophil apoptosis: relevance to the innate immune response and inflammatory disease. J Innate Immun 2(3):216–227CrossRefGoogle Scholar
  9. Ginhoux F, Jung S (2014) Monocytes and macrophages: developmental pathways and tissue homeostasis. Nat Rev Immunol 14(6):392–404CrossRefGoogle Scholar
  10. Hua S, Cabot PJ (2010) Mechanisms of peripheral immune-cell-mediated analgesia in inflammation: clinical and therapeutic implications. Trends Pharmacol Sci 31:427–433CrossRefGoogle Scholar
  11. Ji RR, Chamessian A, Zhang YQ (2016) Pain regulation by nonneuronal cells and inflammation. Science 354:572–577CrossRefGoogle Scholar
  12. Kawanishi N, Mizokami T, Niihara H, Yada K, Suzuki K (2015) Macrophage depletion by clodronate liposome attenuates muscle injury and inflammation following exhaustive exercise. Biochem Biophys Rep 5:146–151Google Scholar
  13. Kidd BL, Urban LA (2001) Mechanisms of inflammatory pain. Br J Anaesth 87(1):3–11CrossRefGoogle Scholar
  14. Kolaczkowska E, Kubes P (2013) Neutrophil recruitment and function in health and inflammation. Nat Rev Immunol 13:159–175CrossRefGoogle Scholar
  15. Lemmer S, Schiesser P, Geis C, Sommer C, Vanegas H, Üçeyler N (2015) Enhanced spinal neuronal responses as a mechanism for the increased nociceptive sensitivity of interleukin-4 deficient mice. Exp Neurol 271:198–204CrossRefGoogle Scholar
  16. Llorian-Salvador M, Gonzalez-Rodriguez S, Lastra A, Fernandez-Garcia MT, Hidalgo A, Menendez L, Baamonde A (2016) Involvement of CC Chemokine Receptor 1 and CCL3 in Acute and Chronic Inflammatory Pain in Mice. Basic Clin Pharmacol Toxicol 119(1):32–40CrossRefGoogle Scholar
  17. Mert T, Gunay I, Ocal I, Guzel AI, Inal TC, Sencar L, Polat S (2009) Macrophage depletion delays progression of neuropathic pain in diabetic animals. Naunyn Schmiedebergs Arch Pharmacol 379:445–452CrossRefGoogle Scholar
  18. Mert T, Ocal I, Gunay I (2014a) Pain relieving effects of pulsed magnetic fields in a rat model of carrageenan-induced hindpaw inflammation. Int J Rad Biol 90(1):95–103CrossRefGoogle Scholar
  19. Mert T, Tugtag B, Kilinc M, Sahin E, Oksuz H, Gunes Y (2014b) Preventive and therapeutic effects of a beta adrenoreceptor agonist, dobutamine, in carrageenan-induced inflammatory nociception in rats. Inflammation 90(1):95–103Google Scholar
  20. Miller RJ, Jung H, Bhangoo SK, White FA (2009) Cytokine and chemokine regulation of sensory neuron function. Handb Exp Pharmacol 194:417–449CrossRefGoogle Scholar
  21. Prame Kumar K, Nicholls AJ, Wong CHY (2018) Partners in crime: neutrophils and monocytes/macrophages in inflammation and disease. Cell Tissue Res 371(3):551–565CrossRefGoogle Scholar
  22. Raoof R, Willemen HLDM, Eijkelkamp N (2018) Divergent roles of immune cells and their mediators in pain. Rheumatology (Oxford) 57(3):429–440CrossRefGoogle Scholar
  23. Ren K, Dubner R (2010) Interactions between the immune and nervous systems in pain. Nat Med 16:1267–1276CrossRefGoogle Scholar
  24. Rittner HL, Machelska H, Stein C (2005) Leukocytes in the regulation of pain and analgesia. J Leukoc Biol 78:1215–1222CrossRefGoogle Scholar
  25. Serhan CN, Savill J (2005) Resolution of inflammation: the beginning programs the end. Nat Immunol 6(12):1191–1197CrossRefGoogle Scholar
  26. Steen-Louws C, Hartgring SAY, Popov-Celeketic J, Lopes AP, de Smet MBM, Eijkelkamp N, Lafeber FPJG, Hack CE, van Roon JAG (2016) IL4-10 fusion protein is a novel drug to treat persistent inflammatory pain. J Neurosci 36:7353–7363CrossRefGoogle Scholar
  27. Suo J, Linke B, Meyer dos Santos S, Pierre S, Stegner D, Zhang DD, Denis CV, Geisslinger G, Nieswandt B, Scholich K (2014) Neutrophils mediate edema formation but not mechanical allodynia during zymosan-induced inflammation. J Leukoc Biol 96(1):133–142CrossRefGoogle Scholar
  28. Tejada MA, Montilla-Garcia A, Cronin SJ, Cikes D, Sanchez-Fernandez C, Gonzalez-Cano R, Ruiz-Cantero MC, Penninger JM, Vela JM, Baeyens JM, Cobos EJ (2017) Sigma-1 receptors control immune-driven peripheral opioid analgesia during inflammation in mice. Proc Natl Acad Sci USA 114(31):8396–8401CrossRefGoogle Scholar
  29. Willemen HL, Eijkelkamp N, Garza Carbajal A, Wang H, Mack M, Zijlstra J, Heijnen CJ, Kavelaars A (2014) Monocytes/macrophages control resolution of transient inflammatory pain. J Pain 15(5):496–506CrossRefGoogle Scholar
  30. Zhang JM, An J (2007) Cytokines, inflammation, and pain. Int Anesthesiol Clin 45:27–37CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Tufan Mert
    • 1
    Email author
  • Mehmet Sahin
    • 2
  • Emel Sahin
    • 2
  • Selma Yaman
    • 3
  1. 1.Department of Biophysics, Faculty of MedicineBolu Abant Izzet Baysal UniversityBoluTurkey
  2. 2.Department of Medical Biology, Faculty of MedicineGaziantep UniversityGaziantepTurkey
  3. 3.Department of Biophysics, Faculty of MedicineKahramanmaras Sutcu Imam UniversityKahramanmarasTurkey

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