Institut National de la Santé et de la Recherche Médicale (Inserm), Unit 970, Paris Cardiovascular Research Center, and Université Paris-Descartes, Paris, France.
Arterioscler Thromb Vasc Biol. 2013 Mar;33(3):581-4. doi: 10.1161/ATVBAHA.112.300516. Epub 2013 Jan 17.
Mutations of signal transducer and activator of transcription 3 (STAT3) are responsible for autosomal dominant hyperimmunoglobulin E syndrome. Recently, we reported frequent vascular abnormalities, including aneurysms in these patients, and demonstrated that STAT3 inhibition promoted aneurysm in mice. The purpose of this study was to investigate the role of cell-specific STAT3 signaling in the susceptibility to aneurysm.
C57BL/6 wild-type mice were irradiated and repopulated with bone marrow cells isolated from either wild-type mice or from mice with defective STAT3 signaling as a result of overexpression of suppressor of cytokine signaling 3 (SOCS3-Tg mice). Mice were then subjected to a validated model of abdominal aortic aneurysm induced by angiotensin II infusion for 28 days, along with repetitive injections of a neutralizing antitransforming growth factor-β antibody. We found that overexpression of SOCS3 in bone marrow-derived cells significantly increased aneurysm severity (P=0.04). In contrast, overexpression of SOCS3 in the vessel wall had no effect on the disease process. Surprisingly, deletion of STAT3 signaling in macrophages did not affect aneurysm development. Interestingly, however, defective STAT3 signaling in SOCS3-Tg T cells markedly increased aneurysm severity (P=0.01) and mortality from aneurysm rupture (P=0.008). Overexpression of SOCS3 in T cells significantly decreased interleukin-17 production (P<0.0001) and was associated with a reduction of its plasma levels (P=0.02).
These findings clearly identify a central role for T cell-specific STAT3 signaling in the promotion of vascular aneurysm and support previous work on interleukin-17 protective role in this process.
信号转导子和转录激活子 3（STAT3）的突变导致常染色体显性遗传性高免疫球蛋白 E 综合征。最近，我们报道了这些患者经常出现血管异常，包括动脉瘤，并且证明 STAT3 抑制可促进小鼠的动脉瘤形成。本研究的目的是研究细胞特异性 STAT3 信号在易患动脉瘤中的作用。
用野生型小鼠或由于细胞因子信号转导抑制因子 3（SOCS3-Tg 小鼠）过表达而导致 STAT3 信号传导缺陷的骨髓细胞分离物辐照和重建成 C57BL/6 野生型小鼠。然后，通过血管紧张素 II 输注 28 天和重复注射中和转化生长因子-β抗体，将小鼠置于已验证的腹主动脉瘤模型中。我们发现骨髓源性细胞中 SOCS3 的过表达显着增加了动脉瘤的严重程度（P=0.04）。相反，血管壁中 SOCS3 的过表达对疾病过程没有影响。令人惊讶的是，巨噬细胞中 STAT3 信号的缺失并未影响动脉瘤的发展。然而，有趣的是，SOCS3-Tg T 细胞中 STAT3 信号的缺陷显着增加了动脉瘤的严重程度（P=0.01）和动脉瘤破裂导致的死亡率（P=0.008）。SOCS3 在 T 细胞中的过表达显着降低了白细胞介素-17 的产生（P<0.0001），并与血浆水平降低相关（P=0.02）。
这些发现清楚地确定了 T 细胞特异性 STAT3 信号在促进血管动脉瘤中的核心作用，并支持了白细胞介素-17 在该过程中的保护作用的先前工作。
