2. Academic Validation
  3. 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

  • Cell Death Dis. 2020 Jan 30;11(1):78. doi: 10.1038/s41419-020-2281-y.
Haojing Liu  # 1,  Fangxiong Cheng  # 2,  Qiang Xu  # 3,  Wei Huang 3,  Sumei Wang 3,  Rui Sun 4,  Duyun Ye 5,  Dongxin Zhang 6
Affiliations

Affiliations

  • 1 Department of Rheumatology and Immunology, Wuhan Fourth Hospital, Puai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430033, PR China.
  • 2 Department of Clinical Laboratory, Wuhan Fourth Hospital, Puai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430033, PR China.
  • 3 Department of Pathophysiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, PR China.
  • 4 Department of Oncology, Wuhan Fourth Hospital, Puai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430033, PR China.
  • 5 Department of Pathophysiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, PR China. yedy@mails.tjmu.edu.cn.
  • 6 Department of Clinical Laboratory, Wuhan Fourth Hospital, Puai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430033, PR China. biozdx@163.com.
  • # Contributed equally.
PMID: 32001671 DOI: 10.1038/s41419-020-2281-y
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.

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