Unleashing PD-1: a duel of immunity in aortic aneurysm formation
Zhenguo Wang, Y. Eugene Chen, Lin Chang
Zhenguo Wang, Y. Eugene Chen, Lin Chang
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Commentary

Unleashing PD-1: a duel of immunity in aortic aneurysm formation

Abstract

Aortic aneurysms, particularly abdominal aortic aneurysms (AAAs), exhibit sex differences, with higher prevalence and severity in males than females, both in humans and experimental mouse models. In fact, male sex has been considered as the most potent nonmodifiable risk factor for AAA. Currently, there are no medications approved for the treatment of aortic aneurysms, despite the high lethality of ruptured aneurysms, which account for nearly 2% of all deaths. Moreover, the underlying molecular mechanisms mediating the sexual dimorphism of aortic aneurysms remain largely unknown. In this issue of the JCI, Mu et al. revealed a mechanism by which androgens, male sex hormones, exacerbate aortic aneurysms by suppressing programmed cell death protein 1 (PD-1) expression in T cells in an aldosterone and high salt–induced aortic aneurysm mouse model.

Authors

Zhenguo Wang, Y. Eugene Chen, Lin Chang

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Figure 1

Sex hormones have differential effects on AA pathogenesis.

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Sex hormones have differential effects on AA pathogenesis. Sex hormones ...
Sex hormones have differential effects on aortic aneurysms pathogenesis. (A) Androgens promote the formation of AAA by increasing angiotensin II type 1a receptor (AT1aR), angiotensin-converting enzyme (ACE), IL-1α, and TGF-β1 signaling, as well as macrophage (Mφ) infiltration, and by suppressing aortic lysyl oxidase (LOX) activity. Mu et al. (18) identified a mechanism whereby androgen transcriptionally inhibits PD-1 gene expression in T cells within the spleen, rendering T cells into a less activated state. Meanwhile, the androgen induces IL-6 expression in the aorta. These changes promote the formation of aortic aneurysms in male mice. (B) Estrogens protect female mice from AAA pathogenesis by increasing LOX and ACE2 expression and promoting Mas receptor (MasR) signaling.