CGAS-STING Plays A Critical Role In The Development Of Abdominal Aortic Aneurysm And Dissection

Background and Aim:Abdominal aortic aneurysms and dissections（AADs）caused by inflammatory reactions results in a large number of deaths worldwide each year.Nevertheless,specifically,which signaling pathway and immune cell subsets lead to the aortic dilatation,intramural hematoma formation,and aortic rupture remains unclear.Here,in a murine model of abdominal aortic aneurysms and dissections（AADs）,we used single-cell RNA sequencing（sc RNA-seq）to elucidate the signaling pathways related to the formation of AADs and provide an essential resource for drug discovery in the future.Methods and Results:To garner an insight into AADs–specific immunomodulatory targets.We harvested specimens of the abdominal aorta with different pathological features at various disease stages from Angiotensin II-infused Apo E^-/-mice and conducted single-cell RNA（sc RNA）sequencing,identified a unique population of interferon-inducible monocytes/macrophages（IFNICs）,which were amply found only in abdominal aortic aneurysmal（AAA）.c GAS-STING and JAK-STAT signaling pathway is activated in IFNICs.Pharmacological blockade of stimulator of interferon genes（STING）with C-176and genetic deletion of STING（bone marrow）in Apo E^-/-mice inhibited the development of intramural hematoma（IMH）and AAA.However,pharmacological blockade of IFN-dependent STING pathway（JAK-STAT signaling pathway）with ruxolitinib or genetic deletion of IFNAR1（Bone marrow）in Apo E^-/-mice only inhibited the development of AAA but not IMH.Moreover,both in vivo and in vitro studies revealed that activation of apoptosis-,pyroptosis-and inflammation-related signaling pathways was implicated in STING-associated vascular inflammation.Conclusion:Cytosolic DNA sensing adaptor STING plays a critical role in the development of AAD in an IFN-dependent or IFN-independent manner.The activation of the IFN-dependent STING pathway induces the formation of IFNICs in AAD,which is significantly related to the formation of AAAs.The IFN-independent STING pathway is related to the formation of IMHs.