Targeting Interleukin-1β Protects from Aortic Aneurysms Induced by Disrupted Transforming Growth Factor β 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 controver- sial roles of transforming growth factor b (TGF-b) signaling in aneurysm development. Here, we report on aneurysms developing in adultmice after smooth muscle cell (SMC)-specific inactivation of Smad4,an intracellular transducer of TGF-b. The results revealed that Smad4 inhibition activated inter- leukin-1b (IL-1b) 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 fa- voring vessel dilation. SMC-specific Smad4 deletion in Il1r1-or Ccr2-null mice resulted in milder aortic pa- thology.A chronic treatment with anti-IL-1b antibody effectively hampered aneurysm development. These findings identify a mechanistic target for controlling the progression of aneurysms with compromised TGF-b signaling, such as those driven by SMAD4 mutations.