Single-cell RNA sequencing identifies interferon-inducible monocytes/macrophages as a cellular target for mitigating the progression of abdominal aortic aneurysm and rupture risk

Abstract Aims Abdominal aortic aneurysm (AAA) represents a life-threatening condition characterized by medial layer degeneration of the abdominal aorta. Nevertheless, knowledge regarding changes in regulators associated with aortic status remains incomplete. A thorough understanding of cell types and signalling pathways involved in the development and progression of AAAs is essential for the development of medical therapy. Methods and results We harvested specimens of the abdominal aorta with different pathological features in Angiotensin II (AngII)-infused ApoE−/− mice, conducted scRNA-seq, and identified a unique population of interferon-inducible monocytes/macrophages (IFNICs), which were amply found in the AAAs. Gene set variation analysis revealed that activation of the cytosolic DNA sensing cGAS-STING and JAK-STAT pathways promoted the secretion of type I interferons in monocytes/macrophages and differentiated them into IFNICs. We generated myeloid cell-specific deletion of Sting1 (Lyz2-Cre+/−; Sting1flox/flox) mice and performed bone marrow transplantation and found that myeloid cell-specific deletion of Sting1 or Ifnar1 significantly reduced the incidence of AAA, aortic rupture rate, and diameter of the abdominal aorta. Mechanistically, the activated pyroptosis- and inflammation-related signalling pathways, regulated by IRF7 in IFNICs, play critical roles in the developing AAAs. Conclusion IFNICs are a unique monocyte/macrophage subset implicated in the development of AAAs and aortic rupture.