STAT3 promotes bone fracture healing by enhancing the FOXP3 expression and the suppressive function of regulatory T cells
STAT3 promotes bone fracture healing by enhancing the FOXP3 expression and the suppressive function of regulatory T cells
复制标题
STAT3通过增强FOXP3表达和调节性T细胞的抑制功能促进骨折愈合
DOI：
10.1111/apm.12706
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发表时间：
2017-08-01
期刊：
影响因子：
2.8
通讯作者：
Qian, Hongbo
中科院分区：
文献类型：
--
作者：
Sun, Guojing;Wang, Zhen;Qian, Hongbo
信号转导子和转录激活子 3 (STAT3) 是骨骼系统和免疫系统中的关键信号蛋白。越来越多的证据表明，炎症反应与骨折的愈合过程密切相关，但在此过程中免疫系统是如何调节的尚不清楚。在这项研究中，我们检查了闭合性胫骨骨折成年患者中 STAT3 介导的免疫调节。在所有患者中，STAT3 的表达和激活在术后第 7 天至第 14 天左右达到峰值，并在其余愈合期间逐渐下降。第7天（STAT3表达和磷酸化达到峰值），骨折患者的CD4(+)CD25(+) T细胞在淋巴细胞亚群中呈现最高水平的STAT3激活。因此，我们研究了STAT3在CD4(+)CD25(+) T细胞中的作用。 CD4(+)CD25(+)T细胞的FOXP3表达水平与这些细胞中STAT3磷酸化水平直接相关。 CD4(+)CD25(+)T细胞中STAT3磷酸化水平也与外周血单核细胞中IFN-和TNF-分泌水平呈负相关。抑制STAT3可显着抑制CD4(+)CD25(+) T细胞表达FOXP3和IL-10，以及CD4(+)CD25(+) T细胞抑制T细胞IFN-和TNF-分泌的能力。此外，早期治愈患者的 STAT3 表达和磷酸化水平明显高于晚期治愈患者，这可能是由于早期治愈患者血清中 IL-6 和 IL-10 水平较高。总之，这些数据表明 STAT3 有利于骨折愈合，可能是通过增强 Treg 介导的对抗炎症的抑制来实现的，并表明 STAT3 可用作预后标记物，以识别具有延迟愈合或不愈合风险的其他无法区分的患者。
Signal transducer and activator of transcription 3 (STAT3) is a key signaling protein in the skeletal system as well as in the immune system. Accumulating evidence demonstrates that the inflammatory response is deeply involved in the healing process of bone fractures, but how the immune system is regulated during this process is unclear. In this study, we examined STAT3-mediated regulation of immunity in adult patients with closed tibia fracture. In all patients, the expression and activation of STAT3 peaked at around day 7 to day 14 after surgery, and gradually decreased during the rest of the healing period. At day 7 (peak STAT3 expression and phosphorylation), the CD4(+)CD25(+) T cells from bone fracture patients presented the highest level of STAT3 activation among lymphocyte subsets. Therefore, we investigated the role of STAT3 in CD4(+)CD25(+) T cells. The level of FOXP3 expression by CD4(+)CD25(+) T cells was directly correlated with the level of STAT3 phosphorylation in these cells. The level of STAT3 phosphorylation in CD4(+)CD25(+) T cells was also inversely correlated with the level of IFN- and TNF- secretion in peripheral blood mononuclear cells. Inhibition of STAT3 significantly suppressed FOXP3 and IL-10 expression by CD4(+)CD25(+) T cells, as well as the ability of CD4(+)CD25(+) T cells to suppress T-cell IFN- and TNF- secretion. Furthermore, early healers patients presented significantly higher STAT3 expression and phosphorylation than late healers, possibly due to the higher IL-6 and IL-10 levels in the serum of early healing patients. Together, these data demonstrated that STAT3 was beneficial to bone fracture healing, possibly by enhancing Treg-mediated suppression of counteracting inflammations, and suggested that STAT3 could be used as a prognostic marker to identify otherwise undistinguishable patients at risk of developing delayed union or nonunion.