Abstract
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.
Highlights
Preeclampsia (PE), characterized by maternal hypertension, proteinuria and other systemic disorders occurring after 20 weeks of gestation, remains a leading cause of maternal and neonatal morbidity and mortality[1,2,3,4]
Lipoxin A4 (LXA4) could suppress angiotensin II type 1 receptor autoantibody (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 angiotensin II type 1 receptor (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
To confirm whether AT1-AA expression is correlated with caspase-1 activation in human PE, we determined the levels of AT1-AA and caspase-1 activation and trophoblast pyroptosis in both normal pregnancy and PE women
Summary
Preeclampsia (PE), characterized by maternal hypertension, proteinuria and other systemic disorders occurring after 20 weeks of gestation, remains a leading cause of maternal and neonatal morbidity and mortality[1,2,3,4]. Dying cells are rapidly engulfed by phagocytes, a process that prevents inflammation or autoimmune response against intracellular antigens[14,15]. Liu et al Cell Death and Disease (2020)11:78 healthy individuals during homeostasis yet autoimmunity doesn’t develop, at least in part, because of rapid clearance of dying cells[15,16]. Our previous results together with other findings suggest that accelerated cell death combined with clearance deficiency lead to the accumulation and externalization of autoantigens and autoantibody production[17,18]. Pyroptosis, termed inflammatory necrosis, is a recently identified caspase-1 dependent cell death, and its induction requires two distinct stimuli, exogenous PAMPs (pathogen-associated molecular patterns) and endogenous DAMPs (damage-associated molecular patterns)[21,22,23]
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