Department of Molecular Medicine, University of Padova, Padua 35131, Italy; Department of Molecular Medicine, "Sapienza" University of Rome, 00161 Rome, Italy.
Department of Angiocardioneurology and Translational Medicine, IRCCS Neuromed, 86077 Pozzilli, Italy.
Immunity. 2017 Nov 21;47(5):959-973.e9. doi: 10.1016/j.immuni.2017.10.016. Epub 2017 Nov 14.
Aortic aneurysms are life-threatening conditions with effective treatments mainly limited to emergency surgery or trans-arterial endovascular stent grafts, thus calling for the identification of specific molecular targets. Genetic studies have highlighted controversial roles of transforming growth factor β (TGF-β) signaling in aneurysm development. Here, we report on aneurysms developing in adult mice after smooth muscle cell (SMC)-specific inactivation of Smad4, an intracellular transducer of TGF-β. The results revealed that Smad4 inhibition activated interleukin-1β (IL-1β) in SMCs. This danger signal later recruited innate immunity in the adventitia through chemokine (C-C motif) ligand 2 (CCL2) and modified the mechanical properties of the aortic wall, thus favoring vessel dilation. SMC-specific Smad4 deletion in Il1r1- or Ccr2-null mice resulted in milder aortic pathology. A chronic treatment with anti-IL-1β antibody effectively hampered aneurysm development. These findings identify a mechanistic target for controlling the progression of aneurysms with compromised TGF-β signaling, such as those driven by SMAD4 mutations.
主动脉瘤是危及生命的疾病，有效的治疗方法主要限于紧急手术或经动脉腔内血管支架移植，因此需要确定特定的分子靶点。遗传研究强调了转化生长因子 β（TGF-β）信号在动脉瘤发展中的争议作用。在这里，我们报告了在平滑肌细胞（SMC）特异性失活 Smad4 的成年小鼠中发生的动脉瘤，Smad4 是 TGF-β 的细胞内转导物。结果表明，Smad4 抑制在 SMC 中激活白细胞介素 1β（IL-1β）。这种危险信号后来通过趋化因子（C-C 基序）配体 2（CCL2）在动脉外膜募集先天免疫，并改变了主动脉壁的力学特性，从而有利于血管扩张。在 Il1r1-或 Ccr2-缺陷小鼠中 SMC 特异性 Smad4 缺失导致主动脉病变较轻。慢性使用抗 IL-1β 抗体可有效阻止动脉瘤的发展。这些发现为控制 TGF-β 信号受损的动脉瘤进展提供了一个机制靶点，如由 SMAD4 突变驱动的动脉瘤。
