4 years ago

Targeting Interleukin-1β Protects from Aortic Aneurysms Induced by Disrupted Transforming Growth Factor β Signaling

Targeting Interleukin-1β Protects from Aortic Aneurysms Induced by Disrupted Transforming Growth Factor β Signaling
Lorenzo Carnevale, Giuseppe Lembo, Daniela Carnevale, Paola Braghetta, Giorgio M. Bressan, Iolanda Vinciguerra, Stefania Fardella, Roberta Iacobucci, Marialuisa Perrotta, Dario Bizzotto, Francesco Da Ros, Manuel Casaburo, Raimondo Carnevale, Giuseppe Cifelli

Summary

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.

Publisher URL: http://www.cell.com/immunity/fulltext/S1074-7613(17)30471-5

DOI: 10.1016/j.immuni.2017.10.016

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