Lipoxin A4 suppresses angiotensin II type 1 receptor autoantibody in preeclampsia via modulating caspase-1
Lipoxin A4 suppresses angiotensin II type 1 receptor autoantibody in preeclampsia via modulating caspase-1
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Lipoxin A(4) 通过调节 caspase-1 抑制先兆子痫患者的血管紧张素 II 1 型受体自身抗体
DOI：
10.1038/s41419-020-2281-y
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发表时间：
2020-01-30
影响因子：
9
通讯作者：
Zhang, Dongxin
中科院分区：
文献类型：
--
作者：
Liu, Haojing;Cheng, Fangxiong;Zhang, Dongxin
先兆子痫（PE）仍然是孕产妇和新生儿发病率和死亡率的主要原因。大量研究表明，PE患者体内存在自身抗体，称为血管紧张素II 1型受体自身抗体（AT 1-AA），其导致了PE的主要特征，炎性细胞坏死（如焦亡）可导致自身抗原暴露，刺激自身抗体产生。Caspase-1是炎性小体的中心酶，也是细胞凋亡的关键靶点，可能在AT 1 R暴露和AT 1-AA产生中发挥作用。寻找能够抑制AT 1-AA生成的内源性调节因子，将对PE的治疗起到重要作用。脂氧素A（4）（LXA（4））是一种内源性双重抗炎和促分解脂质介质，可能通过调节半胱氨酸蛋白酶-1来抑制AT 1-AA的产生。因此，我们探索caspase-1是否是AT 1-AA产生所必需的，以及LXA（4）是否通过调节caspase-1来抑制AT 1-AA。PE患者和小鼠发生与caspase-1活化相关的AT 1-AA。Caspase-1缺失导致PE小鼠AT 1-AA减少。与这些发现相一致，我们证实了caspase-1激活，滋养层细胞凋亡和AT 1 R暴露在PE小鼠和滋养层模型，而caspase-1缺乏显示减少滋养层细胞凋亡和AT 1 R暴露在体外和体内。有趣的是，LXA（4）可通过调节caspase-1以及增强巨噬细胞对死亡滋养细胞的吞噬作用来抑制AT 1-AA的产生。这些结果表明，caspase-1通过诱导滋养细胞焦亡和AT 1 R暴露促进AT 1-AA产生，而LXA（4）通过调节caspase-1抑制AT 1-AA产生，支持caspase-1作为减弱AT 1-AA的治疗靶点，LXA（4）保护患者免受AT 1-AA和PE的影响。
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 A(4) (LXA(4)), 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 LXA(4) 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, LXA(4) 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 LXA(4) suppresses AT1-AA production via modulating caspase-1, supporting caspase-1 serving as a therapeutic target for attenuating AT1-AA and LXA(4) protecting patients from AT1-AA and PE.