Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

MicroRNAs, the immune system and rheumatic disease

Abstract

MicroRNAs (miRNAs) are short noncoding RNA molecules that modulate the expression of multiple target genes at the post-transcriptional level and are implicated in a wide array of cellular and developmental processes. In hematopoietic cells, miRNA levels are dynamically regulated during lineage differentiation and also during the course of the immune response. Mouse models have provided good evidence for miRNAs being key players in the establishment of hematopoietic lineages. Furthermore, miRNA-dependent alterations in gene expression in hematopoietic cells are critical for mounting an appropriate immune response to a wide range of pathogens, spontaneously emerging tumors, and autoimmune cells. Deregulation of hematopoietic-specific miRNA expression results in defects in both central and peripheral tolerance, hematopoietic malignancies, and sometimes both. Abnormal expression of miRNAs—which is implicated in inflammation—has also been found in patients with rheumatoid arthritis. These findings identify miRNAs as critical targets for immunomodulatory drug development.

Key Points

  • microRNAs (miRNAs) are small noncoding RNAs that control the expression of a number of genes by post-transcriptionally modulating the expression of key targets

  • miRNAs usually block protein translation or induce degradation of their target mRNAs; however, enhancement of translation of repressed transcripts has also been reported

  • miRNAs display a tissue-specific pattern of expression, and their levels are dynamic during lineage differentiation of hematopoietic cells

  • Mouse models developed so far provide evidence that miRNAs are not only differentially expressed in hematopoietic lineages, but also that they have a physiological role during differentiation processes

  • Altered expression of some miRNAs is found in patients with rheumatoid arthritis

  • miRNAs are promising targets for immunomodulatory drugs

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1: MicroRNA biogenesis.
Figure 2: Lineage-specific microRNAs.

Similar content being viewed by others

References

  1. Lee RC et al. (1993) The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complimentary to lin-14. Cell 75: 843–854

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  3. Lagos-Quintana M et al. (2001) Identification of novel genes coding for small expressed RNAs. Science 294: 853–858

    Article  CAS  PubMed  Google Scholar 

  4. Ambros V (2003) MicroRNA pathways in flies and worms: growth, death, fat, stress, and timing. Cell 113: 673–676

    Article  CAS  PubMed  Google Scholar 

  5. Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116: 281–297

    CAS  PubMed  Google Scholar 

  6. Calin GA et al. (2002) Frequent deletions and down-regulation of micro-RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci USA 99: 15524–15529

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Tili E et al. (2007) miRNAs and their potential for use against cancer and other diseases. Future Oncol 5: 521–537

    Article  Google Scholar 

  8. Calin GA and Croce CM (2006) MicroRNA signatures in human cancers. Nat Rev Cancer 6: 857–866

    Article  CAS  PubMed  Google Scholar 

  9. Gaur A et al. (2007) Characterization of microRNA expression levels and their biological correlates in human cancer cell lines. Cancer Res 67: 2456–2468

    Article  CAS  PubMed  Google Scholar 

  10. Chen CZ et al. (2004) MicroRNAs modulate hematopoietic lineage differentiation. Science 303: 83–86

    Article  CAS  PubMed  Google Scholar 

  11. Monticelli S et al. (2005) MicroRNA profiling of the murine hematopoietic system. Genome Biol 6: R71

    Article  PubMed  PubMed Central  Google Scholar 

  12. Georgantas RW 3rd et al. (2007) CD34+ hematopoietic stem-progenitor cell microRNA expression and function: a circuit diagram of differentiation control. Proc Natl Acad Sci USA 104: 2750–2755

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Neilson JR et al. (2007) Dynamic regulation of miRNA expression in ordered stages of cellular development. Genes Dev 21: 578–589

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Tili E et al. (2007) Modulation of miR-155 and miR-125b levels following lipopolysaccharide/TNF-alpha stimulation and their possible roles in regulating the response to endotoxin shock. J Immunol 179: 5082–5089

    Article  CAS  PubMed  Google Scholar 

  15. Taganov KD et al. (2006) NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc Natl Acad Sci USA 103: 12481–12486

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Zhou B et al. (2007) miR-150, a microRNA expressed in mature B and T cells, blocks early B cell development when expressed prematurely. Proc Natl Acad Sci USA 104: 7080–7085

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Wu H et al. (2007) miRNA profiling of naïve, effector and memory CD8 T cells. PLoS ONE 2: e1020

    Article  PubMed  PubMed Central  Google Scholar 

  18. Michael MZ et al. (2003) Reduced accumulation of specific microRNAs in colorectal neoplasia. Mol Cancer Res 1: 882–891

    CAS  PubMed  Google Scholar 

  19. Pedersen IM et al. (2007) Interferon modulation of cellular microRNAs as an antiviral mechanism. Nature 18: 919–922

    Article  Google Scholar 

  20. Cullen BR (2004) Transcription and processing of human microRNA precursors. Mol Cell 16: 861–865

    Article  CAS  PubMed  Google Scholar 

  21. Raabe T et al. (1998) Relative contribution of transcription and translation to the induction of tumor necrosis factor-alpha by lipopolysaccharide. J Biol Chem 273: 974–980

    Article  CAS  PubMed  Google Scholar 

  22. Vasudevan S et al. (2007) Switching from repression to activation: microRNAs can up-regulate translation. Science 318: 1931–1934

    Article  CAS  PubMed  Google Scholar 

  23. Place FR et al. (2008) MicroRNA-373 induces expression of genes with complementary promoter sequences. Proc Natl Acad Sci USA 105: 1608–1613

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Ventura A et al. (2008) Targeted deletion reveals essential and overlapping functions of the miR-17 through 92 family of miRNA clusters. Cell 132: 875–886

    CAS  PubMed  PubMed Central  Google Scholar 

  25. He L et al. (2005) microRNA polycistron as a potential human oncogene. Nature 435: 828–833

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Xiao C et al. (2008) Lymphoproliferative disease and autoimmunity in mice with increased miR-17-92 expression in lymphocytes. Nat Immunol 9: 405–414

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Xiao C et al. (2007) MiR-150 controls B cell differentiation by targeting the transcription factor c-Myb. Cell 131: 146–159

    Article  CAS  PubMed  Google Scholar 

  28. Eis PS et al. (2005) Accumulation of miR-155 and BIC RNA in human B cell lymphomas. Proc Natl Acad Sci USA 102: 3627–3632

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Tam W et al. (1997) Bic, a novel gene activated by proviral insertions in avian leukosis virus-induced lymphomas, is likely to function through its noncoding RNA. Mol Cell Biol 17: 1490–1502

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Costinean S et al. (2006) Pre-B cell proliferation and lymphoblastic leukemia/high-grade lymphoma in E(mu)-miR155 transgenic mice. Proc Natl Acad Sci USA 103: 7024–7029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Thai TH et al. (2007) Regulation of the germinal center response by microRNA-155. Science 316: 604–608

    Article  CAS  PubMed  Google Scholar 

  32. Rodriguez A et al. (2007) Requirement of bic/microRNA-155 for normal immune function. Science 316: 608–611

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Vigorito E et al. (2007) microRNA-155 regulates the generation of immunoglobulin class-switched plasma cells. Immunity 27: 847–859

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Skalsky RL et al. (2007) Kaposi's sarcoma-associated herpesvirus encodes an ortholog of miR-155. J Virol 81: 12836–12845

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Gironella M et al. (2007) Tumor protein 53-induced nuclear protein 1 expression is repressed by miR-155, and its restoration inhibits pancreatic tumor development. Proc Natl Acad Sci USA 104: 16170–16175

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Li QJ et al. (2007) miR-181a is an intrinsic modulator of T cell sensitivity and selection. Cell 129: 147–161

    Article  CAS  PubMed  Google Scholar 

  37. Kaushansky K (2006) Lineage-specific hematopoietic growth factors. N Engl J Med 354: 2034–2045

    Article  CAS  PubMed  Google Scholar 

  38. Davidson WF et al. (1979) Phenotypic and functional effects of the motheaten gene on murine B and T lymphocytes. J Immunol 122: 884–891

    CAS  PubMed  Google Scholar 

  39. Fazi F et al. (2007) Epigenetic silencing of the myelopoiesis regulator microRNA-223 by the AML1/ETO oncoprotein. Cancer Cell 12: 457–466

    Article  CAS  PubMed  Google Scholar 

  40. Johnnidis JB et al. (2008) Regulation of progenitor cell proliferation and granulocyte function by microRNA-223. Nature 451: 1125–1129

    Article  CAS  PubMed  Google Scholar 

  41. Nakasa T et al. (2008) Expression of microRNA-146 in rheumatoid arthritis synovial tissue. Arthritis Rheum 58: 1284–1292

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Stanczyk J et al. (2008) Altered expression of MicroRNA in synovial fibroblasts and synovial tissue in rheumatoid arthritis. Arthritis Rheum 58: 1001–1009

    Article  PubMed  Google Scholar 

  43. Targetscan [http://www.targetscan.org]

  44. Jacob CO et al. (1996) Mutational analysis of TNF-alpha gene reveals a regulatory role for the 3′-untranslated region in the genetic predisposition to lupus-like autoimmune disease. J Immunol 156: 3043–3050

    CAS  PubMed  Google Scholar 

  45. Calin GA et al. (2005) A MicroRNA signature associated with prognosis and progression in chronic lymphocytic leukemia. N. Engl J Med 353: 1793–1801

    Article  CAS  PubMed  Google Scholar 

  46. Jakymiw A et al. (2006) Autoimmune targeting of key components of RNA interference. Arthritis Res Ther 8: R87

    Article  PubMed  PubMed Central  Google Scholar 

  47. Yu D et al. (2007) Roquin represses autoimmunity by limiting inducible T-cell co-stimulator messenger RNA. Nature 450: 299–303

    Article  CAS  PubMed  Google Scholar 

  48. Leirisalo-Repo M (2005) Early arthritis and infection. Curr Opin Rheumatol 17: 433–439

    Article  PubMed  Google Scholar 

  49. Callan MF (2004) Epstein–Barr virus, arthritis, and the development of lymphoma in arthritis patients. Curr Opin Rheumatol 6: 399–405

    Article  Google Scholar 

  50. Stern-Ginossar N et al. (2007) Host immune system gene targeting by a viral miRNA. Science 317: 376–381

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Gottwein E et al. (2007) A viral microRNA functions as an orthologue of cellular miR-155. Nature 450: 1096–1099

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Ramkissoon SH et al. (2006) Hematopoietic-specific microRNA expression in human cells. Leuk Res 30: 643–647

    Article  CAS  PubMed  Google Scholar 

  53. Elmén J et al. (2008) LNA-mediated microRNA silencing in non-human primates. Nature 452: 896–899

    Article  PubMed  Google Scholar 

  54. Chen XM et al. (2007) A cellular micro-RNA, let-7i, regulates Toll-like receptor 4 expression and contributes to cholangiocyte immune responses against Cryptosporidium parvum infection. J Biol Chem 282: 28929–28938

    Article  CAS  PubMed  Google Scholar 

  55. O'Donnell KA et al. (2005) c-Myc-regulated microRNAs modulate E2F1 expression. Nature 435: 839–843

    Article  CAS  PubMed  Google Scholar 

  56. Hariharan M et al. (2005) Targets for human encoded microRNAs in HIV genes. Biochem Biophys Res Commun 337: 1214–1218

    Article  CAS  PubMed  Google Scholar 

  57. Dore LC et al. (2008) A GATA-1-regulated microRNA locus essential for erythropoiesis. Proc Natl Acad Sci USA 105: 3333–3338

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Yin Q et al. (2008) B-cell receptor activation induces BIC/miR-155 expression through a conserved AP-1 element. J Biol Chem 283: 2654–2662

    Article  CAS  PubMed  Google Scholar 

  59. Naguibneva I et al. (2006) The microRNA miR-181 targets the homeobox protein Hox-A11 during mammalian myoblast differentiation. Nat Cell Biol 8: 278–284

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Carlo M Croce.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tili, E., Michaille, JJ., Costinean, S. et al. MicroRNAs, the immune system and rheumatic disease. Nat Rev Rheumatol 4, 534–541 (2008). https://doi.org/10.1038/ncprheum0885

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncprheum0885

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing