Lipoxin A4 suppresses angiotensin II type 1 receptor autoantibody in preeclampsia via modulating caspase-1

Preeclampsia (PE) remains a leading cause of maternal and neonatal morbidity and mortality. Numerous studies have shown that women with PE develop autoantibody, termed angiotensin II type 1 receptor autoantibody (AT1-AA), and key features of the disease result from it. Emerging evidence has indicated that inflammatory cell necrosis, such as Pyroptosis, could lead to autoantigen exposure and stimulate autoantibody production. Caspase-1, the central Enzyme of inflammasome and key target of Pyroptosis, may play roles in AT1R exposure and AT1-AA production. Exploring endogenous regulator that could inhibit AT1-AA production by targeting Pyroptosis will be essential for treating PE. Lipoxin A₄ (LXA₄), endogenous dual anti-inflammatory and proresolving lipid mediator, may inhibit AT1-AA production via modulating Caspase-1. Thus, we explore whether Caspase-1 is essential for AT1-AA production and LXA₄ inhibits AT1-AA via modulating Caspase-1. PE patients and mice developed AT1-AA associated with Caspase-1 activation. Caspase-1 deletion leaded to AT1-AA decrease in PE mice. Consistent with these findings, we confirmed Caspase-1 activation, trophoblast Pyroptosis and AT1R exposure in PE mice and trophoblast model, while Caspase-1 deficiency showed decreased trophoblast Pyroptosis and AT1R exposure in vitro and in vivo. Interestingly, LXA₄ could suppress AT1-AA production via regulating Caspase-1 as well as enhancing phagocytosis of dead trophoblasts by macrophages. These results suggest that Caspase-1 promotes AT1-AA production via inducing trophoblast Pyroptosis and AT1R exposure, while LXA₄ suppresses AT1-AA production via modulating Caspase-1, supporting Caspase-1 serving as a therapeutic target for attenuating AT1-AA and LXA₄ protecting patients from AT1-AA and PE.