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. TGF-β signaling has an unquestionable but still controversial role in the pathogenesis of aortic aneurysm. Da Ros et al. demonstrate that disruption of TGF-β signaling in SMCs activates an autocrine IL-1β pathway that acts as a danger signal to recruit innate immune cells in the adventitia through CCL2.
Original language | English |
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Pages (from-to) | 959-973.e9 |
Journal | Immunity |
Volume | 47 |
Issue number | 5 |
DOIs | |
Publication status | Published - Nov 21 2017 |
Keywords
- aortic aneurysm
- CCR2
- elastic lamellae
- IL-1β
- innate immunity
- macrophages
- MCP1
- SMAD4
- smooth muscle cells
- TGF-β
ASJC Scopus subject areas
- Immunology and Allergy
- Immunology
- Infectious Diseases