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

Francesco Da Ros, Raimondo Carnevale, Giuseppe Cifelli, Dario Bizzotto, Manuel Casaburo, Marialuisa Perrotta, Lorenzo Carnevale, Iolanda Vinciguerra, Stefania Fardella, Roberta Iacobucci, Giorgio M. Bressan, Paola Braghetta, Giuseppe Lembo, Daniela Carnevale

Research output: Contribution to journalArticlepeer-review

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 languageEnglish
Pages (from-to)959-973.e9
JournalImmunity
Volume47
Issue number5
DOIs
Publication statusPublished - 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

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