Targeting Interleukin-1\uce\ub2 Protects from Aortic Aneurysms Induced by Disrupted Transforming Growth Factor \uce\ub2 Signaling

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 \u3b2 (TGF-\u3b2) 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-\u3b2. The results revealed that Smad4 inhibition activated interleukin-1\u3b2 (IL-1\u3b2) 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-1\u3b2 antibody effectively hampered aneurysm development. These findings identify a mechanistic target for controlling the progression of aneurysms with compromised TGF-\u3b2 signaling, such as those driven by SMAD4 mutations