The enrichment of neutrophil extracellular traps impair the placentas of systemic lupus erythematosus through accumulating decidual NK cells

Meng Jiang,Jiayue Wu,You Wang,Nan Shen,Wen Di,Sihan Lin,Haibo Zhou

doi:10.1038/s41598-021-86390-0

Abstract

Despite the advances made in the management of pregnancies in women with systemic lupus erythematosus (SLE), the rate of adverse pregnancy outcomes is still higher than that in the general population. In the last few years, neutrophil extracellular traps (NETs) were proven to be detrimental in both autoimmune diseases and placental injury. We investigated whether NETs could be detected in the placentas of pregnant individuals with SLE and explored the relationship between NETs and decidual natural killer cells (dNKs), which comprise the majority of immune cells at the maternal–fetal interface, using clinical samples and animal models. In this study, we found that the infiltration of NETs and dNKs, especially CD56+CD16+ NK cells, was significantly increased in pregnant individuals with SLE with placental insufficiency. In the murine models of SLE, the number of dNKs was significantly decreased due to the decreased formation of NETs affected by Ly6G. Moreover, the histopathological placental injury was reduced, with a remarkable increase in fetal birth weight. This study shows that NETs may contribute to immunological disorder in the placenta and the pathological changes in pregnancies with SLE, which provides a research basis for further explorations of the mechanism of SLE in placental impairment.

Highlights

Decidual natural killer cells account for approximately 70% of the immune cells at the maternal–fetal interface, comprise the largest specific immune cell population and decrease with increasing gestational a ge8. dNK cells are distinct from the majority of peripheral blood NK cells
We propose that the infiltration of Neutrophil extracellular traps (NETs) observed in systemic lupus erythematosus (SLE) pregnancies may be a factor underlying defective immune homeostasis that affects the level of dNKs at the maternal–fetal interface
We found that the levels of NETs and dNKs were remarkably increased in the SLE placenta, especially in those with APOs

Summary

Introduction

Decidual natural killer cells (dNKs) account for approximately 70% of the immune cells at the maternal–fetal interface, comprise the largest specific immune cell population and decrease with increasing gestational a ge8. dNK cells are distinct from the majority of peripheral blood NK cells (pNKs). The levels of circulating NK cells are significantly lower in patients with S LE14, the role of dNKs in SLE-APO pathogenesis has rarely been examined. NETs have been shown to intimately shape the adaptive immune response at various levels, including the control of NK cell h omeostasis[28]. It is still unknown whether NETs can cause placental pathology in SLE pregnancy by regulating dNKs. MRL/lpr mice were proposed as a single gene SLE model in 1 97729. MRL/lpr mice spontaneously develop a systemic, CD4+ T cell and macrophage dependent autoimmune disease and their histopathological and clinical features were similar to human SLE, including production of autoantibody and deposition of immune complexes in vital o rgans[30]. In this study, we characterized the distribution of NETs and dNKs in SLE pregnancies and determined the correlation between them in placental impairment

Methods

Results

Conclusion