Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Comment
  • Published:

IL-32-driven neutrophil activation in preeclampsia

Cellular & Molecular Immunology volume 20, pages 976–977 (2023)Cite this article

Subjects

Preeclampsia (PE), a pregnancy-specific syndrome, is the leading cause of maternal and fetal morbidity and mortality and has been labeled the “great obstetrical syndrome” [1, 2]. Although the etiology and pathophysiology of PE are still not precisely understood, uncontrolled excessive inflammatory responses in the maternal decidua basalis and circulation have been identified as key contributors to PE development. It has been established that in contrast to the immunosuppressive state in patients with normal pregnancy [3], preeclamptic patients present exaggerated activation of immune cells in the decidua basalis in response to invasion by extravillous trophoblasts (EVTs); this results in inadequate EVT invasion and spiral artery remodeling, which in turn lead to processes such as oxidative stress and endoplasmic reticulum stress in the placenta. These processes result in disruption of the syncytial architecture and subsequent increased release of syncytiotrophoblasts (STBs), which cover the villi and are in contact with maternal blood. As a result, a large amount of STB fragments, proinflammatory molecules and antiangiogenic factors are released into the maternal circulation, causing maternal systemic inflammation and widespread endothelial dysfunction [1, 2, 4,5,6]. However, significant progress in identifying potential molecular targets in the pathophysiology of PE is underway.

Clinically, an increase in the percentage and aberrant activation of neutrophils in the peripheral blood of PE patients has been noted [7, 8]. There is plenty of evidence showing that excessive neutrophil activation can activate endothelial cells, inducing a proinflammatory and procoagulant phenotype, which is the pathophysiological hallmark of PE. Some researchers have shown that the placental villus culture supernatant, STB microvillous membranes, serum and plasma of PE patients can activate neutrophils and enhance endothelial cell injury [9, 10], suggesting that some molecules derived from the placenta play important roles in neutrophil activation. In searching for such specific molecules, we found that the expression of IL-32, especially IL-32β, was significantly upregulated in the STBs of severe PE (sPE) patients, which is positively correlated with its serum level, indicating that seral IL-32β is largely released from the placenta [11]. IL-32 is a recently discovered inflammatory cytokine that is widely expressed in T lymphocytes, natural killer cells, monocytes/macrophages, epithelial cells, endothelial cells and fibroblasts and can strongly induce the expression of a variety of proinflammatory cytokines and chemokines, including TNF-α, IL-1β, IL-6 and IL-8, in various immune cells [12, 13]. We first demonstrated that IL-32 was strongly expressed on STBs in first-trimester placentas and progressively downregulated as normal pregnancies advanced. However, IL-32 expression was consistently upregulated in STBs in sPE patients. Among the different spliced isoforms of IL-32, we found that IL-32β was the major isoform elevated in the placentas of sPE patients. Importantly, IL-32β highly induced the activation of neutrophils, leading to the release of a large amount of proinflammatory factors such as TNFα, IL-1β, IL-8 and ROS, with the latter resulting in endothelial cell injury. Thus, we provide evidence that IL-32β is one of the most important upstream factors mediating the development of systemic endothelial activation from placental pathology in PE patients.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

References

  1. Brosens I, Puttemans P, Benagiano G. Placental bed research: I. The placental bed: from spiral arteries remodeling to the great obstetrical syndromes. Am J Obstet Gynecol. 2019;221:437–56.

    Article  PubMed  Google Scholar 

  2. Dimitriadis E, Rolnik DL, Zhou W, Estrada-Gutierrez G, Koga K, Francisco R, et al. Pre-eclampsia. Nat Rev Dis Prim. 2023;9:8.

    Article  PubMed  Google Scholar 

  3. Fu B, Li X, Sun R, Tong X, Ling B, Tian Z, et al. Natural killer cells promote immune tolerance by regulating inflammatory TH17 cells at the human maternal-fetal interface. Proc Natl Acad Sci USA 2013;110:E231–240.

    Article  CAS  PubMed  Google Scholar 

  4. Deer E, Herrock O, Campbell N, Cornelius D, Fitzgerald S, Amaral LM, et al. The role of immune cells and mediators in preeclampsia. Nat Rev Nephrol. 2023;19:257–70.

  5. Ding H, Dai Y, Lei Y, Wang Z, Liu D, Li R, et al. Upregulation of CD81 in trophoblasts induces an imbalance of Treg/Th17 cells by promoting IL-6 expression in preeclampsia. Cell Mol Immunol. 2019;16:302–12.

    Article  PubMed  Google Scholar 

  6. Wang Z, Liu D, Dai Y, Li R, Zheng Y, Zhao G, et al. Elevated Placental microRNA-155 Is a Biomarker of a Preeclamptic Subtype. Hypertension. 2023;80:370–84.

    Article  CAS  PubMed  Google Scholar 

  7. Canzoneri BJ, Lewis DF, Groome L, Wang Y. Increased neutrophil numbers account for leukocytosis in women with preeclampsia. Am J Perinatol. 2009;26:729–32.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Tsukimori K, Fukushima K, Tsushima A, Nakano H. Generation of reactive oxygen species by neutrophils and endothelial cell injury in normal and preeclamptic pregnancies. Hypertension. 2005;46:696–700.

    Article  CAS  PubMed  Google Scholar 

  9. Wang Y, Gu Y, Philibert L, Lucas MJ. Neutrophil activation induced by placental factors in normal and pre-eclamptic pregnancies in vitro. Placenta. 2001;22:560–5.

    Article  CAS  PubMed  Google Scholar 

  10. Aly AS, Khandelwal M, Zhao J, Mehmet AH, Sammel MD, Parry S. Neutrophils are stimulated by syncytiotrophoblast microvillous membranes to generate superoxide radicals in women with preeclampsia. Am J Obstet Gynecol. 2004;190:252–8.

    Article  CAS  PubMed  Google Scholar 

  11. Liu D, Li Q, Ding H, Zhao G, Wang Z, Cao C, et al. Placenta-derived IL-32beta activates neutrophils to promote preeclampsia development. Cell Mol Immunol. 2021;18:979–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Hong JT, Son DJ, Lee CK, Yoon DY, Lee DH, Park MH. Interleukin 32, inflammation and cancer. Pharmacol Ther. 2017;174:127–37.

    Article  CAS  PubMed  Google Scholar 

  13. Wang J, Wang Q, Han T, Li YK, Zhu SL, Ao F, et al. Soluble interleukin-6 receptor is elevated during influenza A virus infection and mediates the IL-6 and IL-32 inflammatory cytokine burst. Cell Mol Immunol. 2015;12:633–44.

    Article  CAS  PubMed  Google Scholar 

  14. Liu M, Lin P, Qu M, Zhai R, Zhang L, Zhang L et al. Neutrophil count is a useful marker to predict the severity of preeclampsia. Clin Exp Hypertens. 2022;1–7. Online ahead of print.

  15. Oglak SC, Tunc S, Olmez F. First Trimester Mean Platelet Volume, Neutrophil to Lymphocyte Ratio, and Platelet to Lymphocyte Ratio Values Are Useful Markers for Predicting Preeclampsia. Ochsner J. 2021;21:364–70.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Key R&D Program of China (2021YFC2701603) and Jiangsu Provincial Obstetrics and Gynecology Innovation Center (CXZX202229).

Author information

Authors and Affiliations

  1. National Regional Medical Center for Obstetrics and Gynecology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, 321 Zhongshan Road, 210008, Nanjing, China

    Dan Liu & Yali Hu

Authors
  1. Dan Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yali Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

DL wrote the manuscript draft. YH revised the manuscript. All authors approved the final version.

Corresponding author

Correspondence to Yali Hu.

Ethics declarations

Competing interests

The authors declare no competing interests.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liu, D., Hu, Y. IL-32-driven neutrophil activation in preeclampsia. Cell Mol Immunol 20, 976–977 (2023). https://doi.org/10.1038/s41423-023-01002-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41423-023-01002-3

Search

Advanced search

Quick links