Single cell RNA sequencing reveals a dysbalance of proinflammatory vs. immunosuppressive dendritic cells in mouse and human aortic aneurysms

Immune cell-driven destruction of the aortic wall remains a major contributor of death in patients burdened with aortic aneurysms (AAs). Dendritic cells (DCs) play critical roles in bridging innate and adaptive immunity by orchestrating robust inflammatory responses and concomitantly sustaining immune tolerance. However, the specific roles of DCs in AA pathogenesis remain to be explored. To examine the participation of DCs in AA pathogenesis, we used single-cell RNA sequencing (scRNA-seq) integration analyses to characterize DC heterogeneity and elucidate their putative involvement in AA pathogenesis in several mouse AA models and translate the experimental data to human AAs. Our data reveal that conventional DC2s (cDC2s) constituted the most abundant DC subtypes in both murine and human AAs. Furthermore, cDC1s, plasmacytoid DCs (pDCs) and immunosuppressive mature regulatory DCs (mregDCs) were identified. Within the cDC2 subtypes, the AA tissue environment trained cDC2s and a newly defined DC3s subtype toward highly pro-inflammatory phenotypes. Parallel to the increased prevalence of pro-inflammatory activated cDC2s and DC3s, a significant reduction of the number of mregDCs was observed in mouse AAs. This data revealed that the balance between pro- vs. the anti-inflammatory DCs is disrupted in mouse AAs. Thus, therapeutic reconstitution strategies to correct this dysbalance together with protective measures that are already in use in clinical practice may lead to beneficial AA outcomes before surgical intervention is needed.