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.
Targeting interleukin-1β protects from aortic aneurysms induced by disrupted transforming growth factor β signaling / DA ROS, Francesco; Carnevale, Raimondo; Cifelli, Giuseppe; Bizzotto, Dario; Casaburo, Manuel; Perrotta, Marialuisa; Carnevale, Lorenzo; Vinciguerra, Iolanda; Fardella, Stefania; Iacobucci, Roberta; Bressan, Giorgio M.; Braghetta, Paola; Lembo, Giuseppe; Carnevale, Daniela. - In: IMMUNITY. - ISSN 1074-7613. - ELETTRONICO. - 47:5(2017), pp. 959-973.e9. [10.1016/j.immuni.2017.10.016]
Targeting interleukin-1β protects from aortic aneurysms induced by disrupted transforming growth factor β signaling
DA ROS, FRANCESCO;Cifelli, Giuseppe;Perrotta, Marialuisa;Lembo, Giuseppe
;Carnevale, Daniela
2017
Abstract
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.File | Dimensione | Formato | |
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