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Can Murine Uterine Natural Killer Cells Give Insights Into the Pathogenesis of Preeclampsia?

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Abstract

These studies aimed to advance understanding of the functions of pregnancy-associated uterinelymphocytes of the natural killer (NK) cell lineage. The approach was morphometric analysis of implantation sites from timed pregnancies in genetically modified mice deficient in NK cells or in signaling associated with their major product, the cytokine interferon-γ. In four different strains of pregnant, NK cell-deficient mice, the major decidual arterioles failed to undergo modifications to their smooth-muscle coats and displayed endothelial cell damage. Decidua lacked normal cell density. This pathology was observed by the end of the first trimester, before placental differentiation. By midgestation in these strains, placentas were smaller than in control strains. In normal mice, many uterine NK cells are perivascular in location and appear to be activated because they are the major sources of interferon-γ and of the interferon-γ-regulated enzyme inducible nitric oxide synthase. During pregnancy in mice genetically ablated for interferon-γ, the interferon-γ receptor chain-α or the transcription factor interferon regulatory factor-1, uterine NK cells differentiate but appear to be abnormal both morphologically and functionally. In these three strains, failure of pregnancy-induced vascular modifications and overt necrosis of decidua occur. Thus, in mice, lymphocytes of the NK cell lineage make specialized contributions to pregnancy-associated modification of the uterine vasculature and to maintenance of decidua. These contributions are achieved through interferon-γ-mediated gene regulation and appear to enhance subsequent placental growth. Human CD56 bright decidual lymphocytes may have analogous functions. If so, changes in numbers or levels of activity of human uterine NK cells or mutations in genes regulated by uterine interferon-γ could contribute to initiation of preeclampsia.

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Authors and Affiliations

  1. Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Ontario, N1G 2W1, Guelph, Canada

    B. Anne Croy DVM, PhD, Ali A. Ashkar DVM, Kanwal Minhas BSc, MSc & James D. Greenwood BSc, MSc, PhD

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  1. B. Anne Croy DVM, PhD
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  2. Ali A. Ashkar DVM
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  3. Kanwal Minhas BSc, MSc
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  4. James D. Greenwood BSc, MSc, PhD
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Correspondence to B. Anne Croy DVM, PhD.

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Supported by awards from the Natural Sciences and Engineering Research Council, Canada, the Ontario Ministry of Agriculture, Food and Rural Affairs, and the Hospital for Sick Children’s Foundation (BAC), and the Ministry of Culture and Higher Education of Iran (AAA).

Helpful discussions with Dr. S. Schneider, Dr. S. Murphy, and Dr. S. Evans of Buffalo and Dr. M. MacLaughlin of Pittsburgh are gratefully acknowledged.

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Croy, B.A., Ashkar, A.A., Minhas, K. et al. Can Murine Uterine Natural Killer Cells Give Insights Into the Pathogenesis of Preeclampsia?. Reprod. Sci. 7, 12–20 (2000). https://doi.org/10.1177/107155760000700104

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