The attenuation of renal fibrosis by histone deacetylase inhibitors is associated with the plasticity of FOXP3(+)IL-17(+) T cells

作者：Wu Wen Pyng; Tsai Yi Giien; Lin Tze Yi; Wu Ming Ju^*; Lin Ching Yuang^*

来源：BMC Nephrology, 2017, 18(1): 225.

DOI：10.1186/s12882-017-0630-6

• Unilateral ureteric obstruction
• Renal fibrosis
• Tgf-beta
• FOXP3(+) IL-17(+) T cells

Background: The histone deacetylase (HDAC) inhibitor, which has potential effects on epigenetic modifications, had been reported to attenuate renal fibrosis. CD4(+) forkhead box P3 (FOXP3)(+) T regulatory (Treg) cells may be converted to inflammation-associated T helper 17 cells (Th17) with tissue fibrosis properties. The association between FOXP3(+) IL-17(+) T cells and the attenuation of renal fibrosis by the HDAC inhibitor is not clear.
Methods: This study evaluated the roles of the HDAC inhibitor, Treg cells and their differentiation into Th17 cells, which aggravate chronic inflammation and renal fibrosis in a unilateral ureteral obstruction (UUO) mouse model. The study groups included control and UUO mice that were monitored for 7, 14 or 21 days.
Results: Juxtaglomerular (JG) hyperplasia, angiotensin II type 1 receptor (AT1R) expression and lymphocyte infiltration were observed in renal tissues after UUO but were decreased after trichostatin A (TSA) treatment, a HDAC inhibitor. The number of CD4(+) FOXP3(+) T cells increased progressively, along with the number of FOXP3(+) interleukin (IL)-17(+) T cells, after 14 days, and their numbers then progressively decreased with increasing CD4(+) IL-17(+) T cell numbers, as demonstrated by double immunohistochemistry. Progressive renal fibrosis was associated with the loss of CD4(+) FOXP3(+) IL-17(+) T cells in splenic single-cell suspensions. FOXP3(+) IL-17(+) T cells expressed TGF-beta 1 both in vitro and in vivo, and TGF-beta 1 expression was significantly knockdown by IL-17 siRNA in vitro. These cells were found to play a role in converting Tregs into IL-17- and TGF-beta 1-producing cells.
Conclusions: TSA treatment decreased JG hyperplasia, the percentage of FOXP3(+) IL-17(+) cells and the degree of fibrosis, suggesting that therapeutic benefits may result from epigenetic modifications.

• 出版日期2017-7-10
• 单位中国医科大学