期刊
JOURNAL OF LEUKOCYTE BIOLOGY
卷 96, 期 5, 页码 675-684出版社
OXFORD UNIV PRESS
DOI: 10.1189/jlb.2HI1113-611RR
关键词
innate immunity; graft rejection; tolerance; Th1 cells; T-regs; glucocorticoids
资金
- National Natural Science Foundation for General Programs of China [31171407, 81273201, 81271907]
- Key Basic Research Project of the Science and Technology Commission of Shanghai Municipality [12JC1400900]
- Innovation Program of Shanghai Municipal Education Commission [14Z Z009]
- Excellent Youth Foundation of Chinese Academy of Sciences [KSCX2-EW-Q-7]
- National Science Foundation for Fostering Talents in Basic Research, National Natural Science Foundation of China [J1210041]
Whereas GCs have been demonstrated to be beneficial for transplantation patients, the pharmacological mechanisms remain unknown. Herein, the role of GR signaling was investigated via a pharmacological approach in a murine allogeneic skin transplantation model. The GC Dex, a representative GC, significantly relieved allograft rejection. In Dex-treated allograft recipient mice, CD11b(+)Gr1(+) MDSCs prolonged graft survival and acted as functional suppressive immune modulators that resulted in fewer IFN-gamma-producing Th1 cells and a greater number of IL-4-producing Th2 cells. In agreement, Dextreated MDSCs promoted reciprocal differentiation between Th1 and Th2 in vivo. Importantly, the GR is required in the Dex-induced MDSC effects. The blocking of GR with RU486 significantly diminished the expression of CXCR2 and the recruitment of CD11b(+)Gr1(+) MDSCs, thereby recovering the increased MDSC-suppressive activity induced by Dex. Mechanistically, Dex treatment induced MDSC iNOS expression and NO production. Pharmacologic inhibition of iNOS completely eliminated the MDSC-suppressive function and the effects on T cell differentiation. This study shows MDSCs to be an essential component in the prolongation of allograft survival following Dex or RU486 treatment, validating the GC-GR-NO signaling axis as a potential therapeutic target in transplantation.
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