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

Immunity | Nov 21, 2017

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.

Pubmed ID: 29150241 RIS Download

Mesh terms: Animals | Aortic Aneurysm | Cells, Cultured | Chemokine CCL2 | Interleukin-1beta | Mice | Myocytes, Smooth Muscle | NF-kappa B | Receptors, CCR2 | Signal Transduction | Smad4 Protein | Tamoxifen | Transforming Growth Factor beta

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