An Estrogen-IL-33 Circuit in Aortic Fibroblasts Underlies Sex Differences in Tregs in Abdominal Aortic Aneurysm.

Regulatory T cells (Tregs) are key components of the vascular immune microenvironment in abdominal aortic aneurysm (AAA), but their sexual dimorphism and underlying mechanisms remain unclear. This study aimed to characterize Treg sex dimorphism in AAA and delineate the governing hormonal and immunologic pathways. Female mice showed reduced aortic Treg infiltration with decreased activation markers (ST2, KLRG1) and the functional mediators interleukin (IL)-10 and trefoil factor 1. Transcriptomic profiling revealed that male aortic Tregs displayed authentic tissue-resident signatures, whereas female aortic Tregs transcriptomically resembled splenic Tregs. Mechanistically, male-biased inflammation stimulated fibroblast IL-33 production via the nuclear factor-κB (NF-κB) pathway, promoting ST2+ Treg expansion, whereas estrogen signaling through estrogen receptor-α suppressed NF-κB activation (reduced P65 phosphorylation and nuclear translocation), lowering microenvironmental IL-33 and limiting Treg responses. Notably, Treg depletion did not exacerbate female AAA, indicating a minor Treg role for female pathogenesis. Our findings establish a novel estrogen receptor α/NF-κB/IL-33 axis in fibroblasts governing Treg sex dimorphism in AAA.