2nd Medical Clinic, Center for Thrombosis and Hemostasis, University Medical Center of Johannes Gutenberg-University, Mainz, Germany.
Arterioscler Thromb Vasc Biol. 2013 Jun;33(6):1313-9. doi: 10.1161/ATVBAHA.113.301437. Epub 2013 Mar 21.
Immune cells contribute to angiotensin II (ATII)-induced vascular dysfunction and inflammation. Interferon-γ (IFN-γ), an inflammatory cytokine exclusively produced by immune cells, seems to be involved in ATII-driven cardiovascular injury, but the actions and cellular source of IFN-γ remain incompletely understood.
IFN-γ(-/-) and Tbx21(-/-) mice were partially protected from ATII-induced (1 mg/kg per day of ATII, infused subcutaneously by miniosmotic pumps) vascular endothelial and smooth muscle dysfunction, whereas mice overexpressing IFN-γ showed constitutive vascular dysfunction. Absence of T-box expressed in T cells (T-bet), the IFN-γ transcription factor encoded by Tbx21, reduced vascular superoxide and peroxynitrite formation and attenuated expression of nicotinamide adenosine dinucleotide phosphate oxidase subunits as well as inducible NO synthase, monocyte chemoattractant protein 1, and interleukin-12 in aortas of ATII-infused mice. Compared with controls, IFN-γ(-/-) and Tbx21(-/-) mice were characterized by reduced ATII-mediated vascular recruitment of both natural killer (NK)1.1(+) NK-cells as the major producers of IFN-γ and CD11b(+)Gr-1(low) interleukin-12 secreting monocytes. Selective depletion and adoptive transfer experiments identified NK-cells as essential contributors to vascular dysfunction and showed that T-bet(+)lysozyme M(+) myelomonocytic cells were required for NK-cell recruitment into vascular tissue and local IFN-γ production.
We provide first evidence that NK-cells play an essential role in ATII-induced vascular dysfunction. In addition, we disclose the T-bet-IFN-γ pathway and mutual monocyte-NK-cell activation as potential therapeutic targets in cardiovascular disease.
免疫细胞参与血管紧张素 II（Angiotensin II，ATII）诱导的血管功能障碍和炎症。干扰素-γ（Interferon-γ，IFN-γ）是一种免疫细胞特异性产生的炎症细胞因子，似乎参与了 ATII 驱动的心血管损伤，但 IFN-γ 的作用和细胞来源仍不完全清楚。
IFN-γ（-/-）和 Tbx21（-/-）小鼠部分免受 ATII 诱导的血管内皮和平滑肌功能障碍（每天皮下输注 1mg/kg ATII，通过微量渗透泵）的影响，而 IFN-γ 过表达的小鼠则表现出持续的血管功能障碍。T 细胞表达的 T 盒（T-box expressed in T cells，T-bet）缺失（即由 Tbx21 编码的 IFN-γ 转录因子）减少了血管中超氧化物和过氧亚硝酸盐的形成，并减轻了烟酰胺腺嘌呤二核苷酸磷酸氧化酶亚基以及诱导型一氧化氮合酶、单核细胞趋化蛋白 1 和白细胞介素-12 在 ATII 输注小鼠主动脉中的表达。与对照组相比，IFN-γ（-/-）和 Tbx21（-/-）小鼠的特征是 ATII 介导的 NK1.1（+）NK 细胞（主要产生 IFN-γ）和 CD11b（+）Gr-1（低）白细胞介素-12 分泌单核细胞的血管募集减少。选择性耗竭和过继转移实验表明 NK 细胞是血管功能障碍的重要贡献者，并表明 T-bet（+）溶菌酶 M（+）髓样细胞是 NK 细胞募集到血管组织和局部 IFN-γ 产生所必需的。
我们首次提供证据表明 NK 细胞在 ATII 诱导的血管功能障碍中起重要作用。此外，我们揭示了 T-bet-IFN-γ 途径和相互的单核细胞-NK 细胞激活作为心血管疾病的潜在治疗靶点。
