46.12 Self DNA Drives Inflammasome Activation by STING During Aortic Aneurysm and Dissection Development

Y. Wang^1,2, W. Luo^1,2, P. Ren^1,2, J. Guo^1,2, C. Zhang^1,2, L. Zhang^1,2, J. Coselli^1,2,3, Y. Shen^1,2,3, S. LeMaire^{1,2,3  1}Baylor College Of Medicine,Division Of Cardiothoracic Surgery,Houston, TX, USA ²Texas Heart Institute,Department Of Cardiovascular Surgery,Houston, TX, USA ³Baylor College Of Medicine,Cardiovascular Research Institute,Houston, TX, USA

Introduction:
During tissue injury, damaged cells activate inflammatory cells, which promote further injury, leading to disease progression. However, the mechanisms underlying inflammation initiation remain to be illustrated. Here, in a setting of aortic aneurysm and dissection (AAD), we show that self DNA from dying smooth muscle cells drive NLRP3 inflammasome activation and inflammatory response by activating pro-inflammatory cytosolic DNA sensor stimulator of interferon genes (STING) and interferon regulatory transcription factor (IRF3) signaling.

Methods:
The activation of NLRP3 inflammasome, STING and IRF3 were examined in macrophages of aortic tissues from patients with sporadic ascending thoracic AAD (ATAAD). The effects of SMC-derived DNA on macrophage activation and the involvement of STING-IRF3 in the NLRP3 inflammasome activation were examined in cultured macrophages. The role of STING in inflammasome activation and aortic inflammation was further examined in Sting-deficient (Sting^-/-) mice in a sporadic AAD model induced by a high-fat diet and angiotensin II infusion.

Results:
In macrophages of aortic tissues from patients with ATAAD, we observed significant amount of cytosolic DNA and activation of the STING-IRF3 pathway, which was associated with NLRP3 inflammasome activation. In cultured macrophages, the engulfment of SMC-derived DNA activated STING and IRF3, which in turn induced the activation of NLRP3 inflammasome. In the sporadic AAD mouse model, genetically deleting Sting or pharmacologically inhibiting Sting with inhibitor Amlexanox significantly reduced the challenge-induced NLRP3 inflammasome activation and aortic inflammation.

Conclusion:
DNA from damaged SMCs, by triggering macrophage cytosolic DNA sensor STING-IRF3 pathway, activates NLRP3 inflammasome, leading to aortic inflammation. This STING-IRF3 pathway mediates the cross-talk between vascular damage and the inflammasome activation and inflammation induction.