Uterine natural killer cell-mediated immune imbalance impairs uterine vascular remodeling and contributes to adverse pregnancy outcomes in dengue virus-infected mice

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Abstract
Recent studies have shown that dengue virus (DENV) infection during pregnancy is linked to adverse pregnancy outcomes, presenting an emerging clinical challenge with poorly understood pathogenic mechanisms. Uterine vascular remodeling, a critical determinant of successful pregnancy, is predominantly regulated by uterine natural killer (uNK) cells. In this study, we explored the effect of uNK cells on uterine injury in a DENV-induced adverse pregnancy mouse model. Transcriptomic analysis revealed significant dysregulation of uterine vascular remodeling and immune response-related gene expression after DENV-2 infection. Histopathological analysis revealed vascular remodeling disorders characterized by the preservation of vascular smooth muscle and a high level of tight junction protein in the vascular wall, accompanied by abnormal dilation of the lumen. These structural abnormalities coincided with a marked increase in uNK cell infiltration in the uterus. Moreover, the depletion of NK cells with anti-Asialo-GM1 mitigated uterine vascular damage and improved pregnancy outcomes. Single-cell RNA sequencing revealed a subpopulation of uNK cells (uNK2) that is characterized by upregulated expression of cytotoxicity-related genes. We further revealed that monocytes/macrophages (Mon_Macro) serve as intermediates in uNK2-mediated neutrophil (NE) recruitment. The SPP1–CD44 signaling axis is the dominant pathway governing uNK2-Mon_Macro crosstalk, and activated Mon_Macro2 can secrete chemokines such as CXCL2 to recruit NE. These findings provide valuable insights into the pathogenesis of DENV-induced uterine injury and facilitate the development of targeted therapeutic interventions for DENV-associated gestational disorders. IMPORTANCE: Dengue virus (DENV), a globally prevalent mosquito-borne virus, increasingly threatens maternal health because its infection is linked to adverse pregnancy outcomes. However, the mechanisms underlying DENV-induced damage to the uterus remain elusive. This study revealed impaired uterine vascular remodeling and abnormal vascular dilation followin g DENV-2 infection. Notably, uterine natural killer (uNK) cells are the critical pathological determinants of vascular injury in the uterus. Mechanistically, uNK cells may influence monocytes/macrophages (Mon_Macro) through SPP1–CD44 signaling to drive neutrophil infiltration, leading to uterine damage and adverse pregnancy outcomes. Successful depletion of NK cells reduces vascular damage and improves pregnancy outcomes. These findings provide critical mechanistic insights into DENV-2-induced uterine pathological lesions, fundamentally advancing our understanding of mosquito-borne virus-associated gestational diseases. The identified molecular cascades not only reveal the etiological landscape of pregnancy complications but also establish therapeutic measures for intervention strategies in mosquito-borne viral disorders.
Funding Information
  • National Natural Science Foundation of China (32370163)
  • National Natural Science Foundation of China (32400134)
  • Natural Science Foundation of Zhejiang Province (LQN25H190001)

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