2. Academic Validation
  3. Neutrophil extracellular traps induce trophoblasts pyroptosis via enhancing NLRP3 lactylation in SLE pregnancies

Neutrophil extracellular traps induce trophoblasts pyroptosis via enhancing NLRP3 lactylation in SLE pregnancies

  • J Autoimmun. 2025 May:153:103411. doi: 10.1016/j.jaut.2025.103411.
Haoyue Hu 1,  You Peng 1,  Chi Chiu Wang 2,  Jun Chen 1,  Xiao Yu 3,  Xiaoyan Chen 4,  Haotong Ouyang 5,  Qin Huang 6,  Jing Ma 7,  Qian Yin 7,  Lien Ma 5,  Ziling Ding 7,  Minyi Zhang 5,  Hao Ren 6,  Jiaman Zheng 6,  Wenqian Chen 7,  Zixin Tao 7,  Ruiyan Liu 5,  Lu Chen 8,  Xuefei Wang 9,  Tao Zhang 10,  Mei Zhong 11
Affiliations

Affiliations

  • 1 Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China; Department of Obstetrics and Gynaecology, The Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong Special Administrative Region of China.
  • 2 Department of Obstetrics and Gynaecology, Li Ka Shing Institute of Health Sciences, School of Biomedical Sciences, Chinese University of Hong Kong-Sichuan University Joint Laboratory in Reproductive Medicine, The Chinese University of Hong Kong, Hong Kong Special Administrative Region of China.
  • 3 Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China.
  • 4 Maternal-Fetal Medicine Institute, Department of Obstetrics and Gynecology, Shenzhen Baoan Women's and Children's Hospital, Shenzhen, China.
  • 5 Department of Epidemiology, School of Public Health, Southern Medical University, Guangzhou, Guangdong, China.
  • 6 Department of Rheumatology and Immunology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
  • 7 Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
  • 8 Department of Obstetrics and Gynaecology, The Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong Special Administrative Region of China.
  • 9 Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China. Electronic address: 40703078@qq.com.
  • 10 Department of Obstetrics and Gynaecology, The Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong Special Administrative Region of China. Electronic address: taozhang@cuhk.edu.hk.
  • 11 Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China; Sino-US Center of Translational Medicine for Development Disabilities, Southern Medical University, Guangzhou, Guangdong, China.
PMID: 40179478 DOI: 10.1016/j.jaut.2025.103411
Abstract

Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder primarily affecting women during the reproductive years, often complicating pregnancy outcomes with elevated levels of neutrophil extracellular traps (NETs) infiltration. However, potential impacts of NETs on placental trophoblasts in SLE and the underlying molecular mechanisms remain unclear. To address this, transcriptome Sequencing was conducted on placentas collected from seven pregnant women with SLE and six healthy pregnant controls to identify SLE-specific placental features. The effects of NETs were further assessed in MRL/lpr lupus-prone mice and pristane-induced lupus (PIL) mice, focusing on pregnancy outcomes and placental pathology. In vitro, trophoblasts were stimulated with NETs derived from patients with SLE, followed by molecular analyses such as transcriptomic, cellular energy metabolism assays and liquid chromatography-tandem mass spectrometry to explore the effects and mechanisms of NETs. Results showed elevated NETs were observed in the placentas of both patients with SLE and lupus mouse models, accompanied by activation of the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome. Treatment with DNase I significantly improved pregnancy outcomes in MRL/lpr mice, while the use of peptidyl arginine deiminase 4 (PAD4)-deficient mice was beneficial on the pregnancy outcomes of PIL mice. Furthermore, SLE-derived NETs activated Pyroptosis in trophoblasts by promoting glycolysis and subsequent lactylation of NLRP3. These findings highlight that NETs contribute to placental damage in SLE by inducing the lactylation of the NLRP3 inflammasome in trophoblasts, demonstrating the therapeutic potential of inhibiting NETs to improve placental function.

Keywords

Lactylation; NLRP3; Neutrophil extracellular traps; Systemic lupus erythematosus; Trophoblast.

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