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56 Micromanaging lupus nephritis: mir17–92 modulates regulatory t cell activity by targeting foxp3 co-regulators
  1. HY Yang1,
  2. CY Wu2 and
  3. JL Huang2
  1. 1Chang-Gung Memorial Hospital- Linko Branch, Nephrology, Taoyuan, Taiwan R.O.C
  2. 2Chang-Gung Memorial Hospital- Linko Branch, Paediatrics, Taoyuan, Taiwan R.O.C

Abstract

Background and aims Regulatory T (Treg) cells play a critical role in maintaining self-tolerance and controlling the magnitude of physiologic immune response. The Treg transcription factor forkhead box P3 (Foxp3) works in concert with other co-regulator molecules including Eos to determine suppressive phenotype of Treg. We identified miR17-92 cluster targeting Eos through bioinformatics approaches.

Methods We generated T-cell-specific miR-17–92 null (mir17-92 -/-) mice by mating mir17-92flox/flox mutants to CD4-Cre+ transgenic mice. Treg from mir17-92 -/- mice will be isolated, followed by suppression assay to evaluate the role of the miR-17–92 cluster in Treg function. We applied pristane to induce lupus nephropathy in wild type and mir17-92 -/- mice. We examined the up-stream promoter region of miR-17–92 for binding sites of down-stream mediators of IL-6 signalling, verified by chromatin immunoprecipitation assay.

Results The inflammatory cytokine IL-6 unregulated miR17-92 through HIF-1. MiR17-92 cluster.actively suppressed Eos expression. Knockdown of miR17-92 in Treg enhanced their suppressive activity. Mir17-92 T cell specific deficiency mitigated pristane induced-lupus nephropathy associated with diminished Th17 cells and autoantibody. Moreover, histological analysis revealed a lower mean renal histopathology score and less compliment deposition. Ectopic expression of miR-17 downmodulated the suppression functions of Tregs and provided Treg with partial effector activity via the derepression of cytokine genes.

Conclusions Our studies suggest that miR17-92 modulates Treg cell function by targeting Eos and potentially additional Foxp3 co-regulators, unveiling the future therapeutic potential of microRNA manipulation in lupus nephritis.

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