Skip to main content
SpringerLink
Log in

The Use of MiRNA Antagonists in the Alleviation of Inflammatory Disorders

  • Protocol
  • First Online:
Toll-Like Receptors

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1390))

Abstract

Toll-like receptors (TLR), a family of pattern-recognition receptors (PRRs) stimulated by pathogen-associated molecular patterns (PAMPs), generate antigen-triggered innate and adaptive immune responses. Recent studies have indicated that several small, regulatory RNAs, called microRNAs (miRNas), are induced by TLR activation in immune cells and that many microRNAs can control the inflammatory process and response to infection by positively or negatively regulating TLR signaling. Among these miRNAs, aberrant microRNA-155 (miR-155) has been implicated in diverse immune processes including the pathogenesis of several autoimmune diseases and cancer. Here, we discuss the role of miR-155 in TLR-mediated and TLR-related immune system regulation. Furthermore, we present our current knowledge of the design, in vivo delivery strategies, and therapeutic efficacy of miR-155 inhibitors in various inflammatory disorders and cancer, including a protocol on the use of miRNA-155 inhibitors in experimental autoimmune encephalomyelitis (EAE).

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Kawai T, Akira S (2011) Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity 34:637–650

    Article  CAS  PubMed  Google Scholar 

  2. Quinn SR, O'Neill LA (2011) A trio of microRNAs that control Toll-like receptor signalling. Int Immunol 23:421–425

    Article  CAS  PubMed  Google Scholar 

  3. ONeill LA, Sheedy FJ, McCoy CE (2004) MicroRNAs: the fine-tuners of Toll-like receptor signalling. Nat Rev Immunol 11:163–175

    Article  Google Scholar 

  4. Ambros V (2004) The functions of animal microRNAs. Nature 431:350–355

    Article  CAS  PubMed  Google Scholar 

  5. O’Connell RM, Rao DS, Chaudhuri AA et al (2010) Physiological and pathological roles for microRNAs in the immune system. Nat Rev Immunol 10:111–122

    Article  PubMed  Google Scholar 

  6. Cobb BS, Hertweck A, Smith J et al (2006) A role for Dicer in immune regulation. J Exp Med 203:2519–2527

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Zhang N, Bevan MJ (2010) Dicer controls CD8+ T-cell activation, migration, and survival. Proc Natl Acad Sci U S A 107:21629–21734

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Kuipers H, Schnorfeil FM, Fehling HJ et al (2010) Dicer-dependent microRNAs control maturation, function, and maintenance of Langerhans cells in vivo. J Immunol 185:400–409

    Article  CAS  PubMed  Google Scholar 

  9. Lu C, Huang X, Zhang X et al (2011) miR-221 and miR-155 regulate human dendritic cell development, apoptosis, and IL-12 production through targeting of p27kip1, KPC1, and SOCS-1. Blood 117:4293–4303

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. O'Connell RM, Kahn D, Gibson WS et al (2010) MicroRNA-155 promotes autoimmune inflammation by enhancing inflammatory T cell development. Immunity 33:607–19

    Article  PubMed Central  PubMed  Google Scholar 

  11. Murugaiyan G, Beynon V, Mittal A et al (2011) Silencing microRNA-155 ameliorates experimental autoimmune encephalomyelitis. J Immunol 187:2213–2221

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Haasch D, Chen YW, Reilly RM et al (2002) T cell activation induces a noncoding RNA transcript sensitive to inhibition by immunosuppressant drugs and encoded by the proto-oncogene, BIC. Cell Immunol 217:78–86

    Article  CAS  PubMed  Google Scholar 

  13. Kurowska-Stolarska M, Alivernini S, Ballantine LE et al (2011) MicroRNA-155 as a proinflammatory regulator in clinical and experimental arthritis. Proc Natl Acad Sci U S A 108:11193–11198

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Hu R, Huffaker TB, Kagele DA et al (2013) MicroRNA-155 confers encephalogenic potential to Th17 cells by promoting effector gene expression. J Immunol 190:5972–5980

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Escobar TM, Kanellopoulou C, Kugler DG et al (2014) miR-155 activates cytokine gene expression in Th17 cells by regulating the DNA-binding protein Jarid2 to relieve polycomb-mediated repression. Immunity 40:865–879

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Thai TH, Calado DP, Casola S et al (2007) Regulation of the germinal center response by microRNA-155. Science 316:604–608

    Article  CAS  PubMed  Google Scholar 

  17. Lu LF, Thai TH, Calado DP et al (2009) Foxp3-dependent microRNA155 confers competitive fitness to regulatory T cells by targeting SOCS1 protein. Immunity 30:80–91

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Kohlhaas S, Garden OA, Scudamore C et al (2009) Cutting edge: the Foxp3 target miR-155 contributes to the development of regulatory T cells. J Immunol 182:2578–2582

    Article  CAS  PubMed  Google Scholar 

  19. Vigorito E, Perks KL, Abreu-Goodger C et al (2007) microRNA-155 regulates the generation of immunoglobulin class-switched plasma cells. Immunity 27:847–859

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Teng G, Hakimpour P, Landgraf P et al (2008) MicroRNA-155 is a negative regulator of activation-induced cytidine deaminase. Immunity 28:621–629

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Rodriguez A, Vigorito E, Clare S et al (2007) Requirement of bic/microRNA-155 for normal immune function. Science 316:608–611

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Oertli M, Engler DB, Kohler E et al (2011) MicroRNA-155 is essential for the T cell-mediated control of Helicobacter pylori infection and for the induction of chronic Gastritis and Colitis. J Immunol 187:3578–3586

    Article  CAS  PubMed  Google Scholar 

  23. Dudda JC, Salaun B, Ji Y et al (2013) MicroRNA-155 is required for effector CD8+ T cell responses to virus infection and cancer. Immunity 38:742–753

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Thounaojam MC, Kundu K, Kaushik DK et al (2014) MicroRNA 155 regulates Japanese encephalitis virus-induced inflammatory response by targeting Src homology 2-containing inositol phosphatase 1. J Virol 88:4798–4810

    Article  PubMed Central  PubMed  Google Scholar 

  25. Eis PS, Tam W, Sun L et al (2005) Accumulation of miR-155 and BIC RNA in human B cell lymphomas. Proc Natl Acad Sci U S A 102:3627–3632

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Kluiver J, Poppema S, de Jong D et al (2005) BIC and miR-155 are highly expressed in Hodgkin, primary mediastinal and diffuse large B cell lymphomas. J Pathol 207:243–249

    Article  CAS  PubMed  Google Scholar 

  27. O'Connell RM, Rao DS, Chaudhuri AA et al (2008) Sustained expression of microRNA-155 in hematopoietic stem cells causes a myeloproliferative disorder. J Exp Med 205:585–594

    Article  PubMed Central  PubMed  Google Scholar 

  28. Leng RX, Pan HF, Qin WZ (2011) Role of microRNA-155 in autoimmunity. Cytokine Growth Factor Rev 22:141–147

    Article  CAS  PubMed  Google Scholar 

  29. Junker A, Krumbholz M, Eisele S et al (2009) MicroRNA profiling of multiple sclerosis lesions identifies modulators of the regulatory protein CD47. Brain 132:3342–3352

    Article  PubMed  Google Scholar 

  30. Moore CS, Rao VT, Durafourt BA et al (2013) miR-155 as a multiple sclerosis-relevant regulator of myeloid cell polarization. Ann Neurol 74:709–720

    Article  CAS  PubMed  Google Scholar 

  31. Blüml S, Bonelli M, Niederreiter B et al (2011) Essential role of microRNA-155 in the pathogenesis of autoimmune arthritis in mice. Arthritis Rheum 63:1281–1288

    Article  PubMed  Google Scholar 

  32. Malmhäll C, Alawieh S, Lu Y et al (2014) Allergy microRNA-155 is essential for T(H)2-mediated allergen-induced eosinophilic inflammation in the lung. J Allergy Clin Immunol 133:1429–1438

    Article  PubMed  Google Scholar 

  33. Singh UP, Murphy AE, Enos RT et al (2014) miR-155 deficiency protects mice from experimental colitis by reducing T helper type 1/type 17 responses. Immunology 143:478–489

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Comer BS, Camoretti-Mercado B, Kogut PC et al (2014) Cyclooxygenase-2 and microRNA-155 expression are elevated in asthmatic airway smooth muscle cells. Am J Respir Cell Mol Biol 52:438–447

    Article  Google Scholar 

  35. Min M, Peng L, Yang Y et al (2014) MicroRNA-155 is involved in the pathogenesis of ulcerative colitis by targeting FOXO3a. Inflamm Bowel Dis 20:652–659

    Article  PubMed  Google Scholar 

  36. Lennox KA, Behlke MA (2010) A direct comparison of anti-microRNA oligonucleotide potency. Pharm Res 27:1788–1799

    Article  CAS  PubMed  Google Scholar 

  37. Li Z, Rana TM (2014) Therapeutic targeting of microRNAs: current status and future challenges. Nat Rev Drug Discov 13:622–638

    Article  CAS  PubMed  Google Scholar 

  38. van Rooij E, Purcell AL, Levin AA (2012) Developing microRNA therapeutics. Circ Res 110:496–507

    Article  PubMed  Google Scholar 

  39. Petersen M, Bondensgaard K, Wengel J et al (2002) Locked nucleic acid (LNA) recognition of RNA: NMR solution structures of LNA:RNA hybrids. J Am Chem Soc 124:5974–5982

    Article  CAS  PubMed  Google Scholar 

  40. Fabbri E, Brognara E, Borgatti M et al (2011) miRNA therapeutics: delivery and biological activity of peptide nucleic acids targeting miRNAs. Epigenomics 3:733–745

    Article  CAS  PubMed  Google Scholar 

  41. Demidov VV, Potaman VN, Frank-Kamenetskii MD et al (1994) Stability of peptide nucleic acids in human serum and cellular extracts. Biochem Pharmacol 48:1310–1313

    Article  CAS  PubMed  Google Scholar 

  42. Fabani MM, Abreu-Goodger C, Williams D et al (2010) Efficient inhibition of miR-155 function in vivo by peptide nucleic acids. Nucleic Acids Res 38:4466–4475

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  43. Babar IA, Cheng CJ, Booth CJ et al (2012) Nanoparticle-based therapy in an in vivo microRNA-155 (miR-155)-dependent mouse model of lymphoma. Proc Natl Acad Sci U S A 109:E1695–704

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  44. Cheng CJ, Bahal R, Babar IA et al (2015) MicroRNA silencing for cancer therapy targeted to the tumour microenvironment. Nature 518:107–110

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  45. Fabbri E, Manicardi A, Tedeschi T et al (2011) Modulation of the biological activity of microRNA-210 with peptide nucleic acids (PNAs). ChemMedChem 6:2192–2202

    Article  CAS  PubMed  Google Scholar 

  46. Ørom UA, Kauppinen S, Lund AH (2006) LNA-modified oligonucleotides mediate specific inhibition of microRNA function. Gene 372:137–141

    Article  PubMed  Google Scholar 

  47. Elmén J, Lindow M, Schütz S et al (2008) LNA-mediated microRNA silencing in non-human primates. Nature 452:896–899

    Article  PubMed  Google Scholar 

  48. Obad S, dos Santos CO, Petri A, Heidenblad M et al (2011) Silencing of microRNA families by seed-targeting tiny LNAs. Nat Genet 43:371–378

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  49. Zhang Y, Roccaro AM, Rombaoa C et al (2012) LNA-mediated anti-miR-155 silencing in low-grade B-cell lymphomas. Blood 120:1678–1686

    Article  CAS  PubMed  Google Scholar 

  50. Worm J, Stenvang J, Petri A et al (2009) Silencing of microRNA-155 in mice during acute inflammatory response leads to derepression of c/ebp Beta and down-regulation of G-CSF. Nucleic Acids Res 37:5784–5792

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  51. Zhang J, Cheng Y, Cui W et al (2014) MicroRNA-155 modulates Th1 and Th17 cell differentiation and is associated with multiple sclerosis and experimental autoimmune encephalomyelitis. J Neuroimmunol 266:56–63

    Article  CAS  PubMed  Google Scholar 

  52. Butovsky O, Jedrychowski MP, Cialic R et al (2015) Targeting miR-155 restores abnormal microglia and attenuates disease in SOD1 mice. Ann Neurol 77:75–99

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the National Multiple Sclerosis Society (RG 4904A2/1) and the Harvard NeuroDiscovery Center.

Author information

Authors and Affiliations

  1. Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA, 02115, USA

    Lucien P. Garo & Gopal Murugaiyan

Authors
  1. Lucien P. Garo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gopal Murugaiyan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gopal Murugaiyan .

Editor information

Editors and Affiliations

  1. Hudson Institute of Medical Research, Monash University Faculty of Medicine, Clayton, Victoria, Australia

    Claire E. McCoy

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer Science+Business Media New York

About this protocol

Cite this protocol

Garo, L.P., Murugaiyan, G. (2016). The Use of MiRNA Antagonists in the Alleviation of Inflammatory Disorders. In: McCoy, C. (eds) Toll-Like Receptors. Methods in Molecular Biology, vol 1390. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-3335-8_24

Download citation

  • DOI: https://doi.org/10.1007/978-1-4939-3335-8_24

  • Published:

  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4939-3333-4

  • Online ISBN: 978-1-4939-3335-8

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation