Article Text

PDF
A7.19 Systemic inhibition of MIR-148A by antagomirs reduces CD4+ T helper cell numbers and alleviates inflammation in a preclinical model of transfer colitis
  1. P Maschmeyer1,
  2. J Zimmermann1,
  3. CL Tran1,
  4. C Haftmann1,
  5. B Rausch1,
  6. R Riedel1,
  7. S Herzog2,
  8. HD Chang1,
  9. A Radbruch1,*,
  10. MF Mashreghi1,*
  1. 1Deutsches Rheuma-Forschungszentrum (DRFZ) Berlin, Berlin, Germany
  2. 2Division of Developmental Immunology, BIOCENTER, Medical University Innsbruck, Innsbruck, Austria
  3. *Equal Contribution

Abstract

Background and objectives T helper type 1 (Th1) cells are involved in rheumatic diseases such as Crohn´s disease or rheumatoid arthritis and have a history of chronic autoantigenic stimulation. We have shown that Th1 cells adapt to chronic inflammation by upregulating the expression of the microRNA (miR)-148a. MiR-148a promotes the survival of chronically activated Th1 cells by regulating the expression of the proapoptotic protein Bim. Thus, we tested the suitability of miR-148a as a therapeutic target for the selective elimination of proinflammatory Th1 cells in a preclinical model of colitis.

Methods Chronically activated Th1 cells were transferred into Rag1-deficient mice to induce colitis. Then, mice were intravenously injected with antagomirs that specifically target the microRNA-148a (antagomir-148a) or with control antagomirs (antagomir-scr). For assessing the function of T cell-intrinsic expression of miR-148a in colitis, we transduced Th1 cells with inducible microRNA sponges prior to transfer into Rag1-deficient mice. Colitic inflammation was determined by the weight-to-length ratios of colons. Colonic Th cells were sorted by FACS to measure miR-148a expression by qRT-PCR. The expression of Bim and Bcl-2 as well as numbers of viable Th1 cells, were determined by flow cytometry.

Results Systemic inhibition of miR-148a by antagomirs alleviated colitis in mice as measured by reduced weight-to-length ratios of their colons. The numbers of viable Th1 cells were reduced up to 50% in mice that were treated with antagomir-148a when compared to mice that were injected with antagomir-scr. Antagomir-148a injections were efficient and resulted in a 30% reduction of miR-148a in colonic Th1 cells. The expression of the proapoptotic protein Bim was increased up to 30% in Th cells from antagomir-148a treated mice, while the anti-apoptotic protein Bcl-2 was unchanged. Th cell specific inhibition of miR-148a by miR-sponges during colitis led to a 30% reduction of Th cells in the colons of colitic mice and reduced the weight-to-length ratio.

Conclusions We suggest that miR-148a controls the survival of proinflammatory Th1 cells in chronic inflammation by inhibiting Bim expression in a Th cell intrinsic fashion. Thus, miR-148a might represent a suitable target for the selective depletion of proinflammatory Th1 cells in chronic inflammation.

Statistics from Altmetric.com

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.