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Maternal CXCR4 deletion results in placental defects and pregnancy loss mediated by immune dysregulation.

ABSTRACT: CXCR4 is a key regulator of the development of NK cells and DCs, both of which play an important role in early placental development and immune tolerance at the maternal-fetal interface. However, the role of CXCR4 in pregnancy is not well understood. Our study demonstrates that adult-induced global genetic CXCR4 deletion, but not uterine-specific CXCR4 deletion, was associated with increased pregnancy resorptions and decreased litter size. CXCR4-deficient mice had decreased NK cells and increased granulocytes in the decidua, along with increased leukocyte numbers in peripheral blood. We found that CXCR4-deficient mice had abnormal decidual NK cell aggregates and NK cell infiltration into trophoblast areas beyond the giant cell layer. This was associated with low NK cell expression of granzyme B, a NK cell granule effector, indicative of NK cell dysfunction. Pregnancy failure in these mice was associated with abnormalities in placental vascular development and increased placental expression of inflammatory genes. Importantly, adoptive BM transfer of WT CXCR4+ BM cells into CXCR4-deficient mice rescued the reproductive deficits by normalizing NK cell function and mediating normal placental vascular development. Collectively, our study found an important role for maternal CXCR4 expression in immune cell function, placental development, and pregnancy maintenance.

SUBMITTER: Lyu F

PROVIDER: S-EPMC10721256 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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Maternal CXCR4 deletion results in placental defects and pregnancy loss mediated by immune dysregulation.

Lyu Fang F Burzynski Chase C Fang Yuan Yuan YY Tal Aya A Chen Alice Y AY Kisa Jacqueline J Agrawal Kriti K Kluger Yuval Y Taylor Hugh S HS Tal Reshef R

JCI insight 20231108 21

CXCR4 is a key regulator of the development of NK cells and DCs, both of which play an important role in early placental development and immune tolerance at the maternal-fetal interface. However, the role of CXCR4 in pregnancy is not well understood. Our study demonstrates that adult-induced global genetic CXCR4 deletion, but not uterine-specific CXCR4 deletion, was associated with increased pregnancy resorptions and decreased litter size. CXCR4-deficient mice had decreased NK cells and increase ...[more]

PMID: 37815869

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Project description:IntroductionProgranulin (PGRN) is a secreted glycoprotein, the expression of which is linked to several neurodegenerative diseases. Although its specific function is still unclear, several studies have linked it with lysosomal functions and immune system regulation. Here, we have explored the role of PGRN in peripheral and central immune system homeostasis by investigating the consequences of PGRN deficiency on adaptive and innate immune cell populations.MethodsFirst, we used gene co-expression network analysis of published data to test the hypothesis that Grn has a critical role in regulating the activation status of immune cell populations in both central and peripheral compartments. To investigate the extent to which PGRN-deficiency resulted in immune dysregulation, we performed deep immunophenotyping by flow cytometry of 19-24-month old male and female Grn-deficient mice (PGRN KO) and littermate Grn-sufficient controls (WT).ResultsMale PGRN KO mice exhibited a lower abundance of microglial cells with higher MHC-II expression, increased CD44 expression on monocytes in the brain, and more CNS-associated CD8+ T cells compared to WT mice. Furthermore, we observed an increase in CD44 on CD8+ T cells in the peripheral blood. Female PGRN KO mice also had fewer microglia compared to WT mice, and we also observed reduced expression of MHC-II on brain monocytes. Additionally, we found an increase in Ly-6Chigh monocyte frequency and decreased CD44 expression on CD8+ and CD4+ T cells in PGRN KO female blood. Given that Gpnmb, which encodes for the lysosomal protein Glycoprotein non-metastatic melanoma protein B, has been reported to be upregulated in PGRN KO mice, we investigated changes in GPNMB protein expression associated with PGRN deficits and found that GPNMB is modulated in myeloid cells in a sex-specific manner.DiscussionOur data suggest that PGRN and GPNMB jointly regulate the peripheral and the central immune system in a sex-specific manner; thus, understanding their associated mechanisms could pave the way for developing new neuroprotective strategies to modulate central and peripheral inflammation to lower risk for neurodegenerative diseases and possibly delay or halt progression.

Project description:Adaptive immune system, principally governed by the T cells-dendritic cells (DCs) nexus, is an essential mediator of gestational fetal tolerance and protection against infection. However, the exact composition and dynamics of DCs and T cell subsets in gestational tissues are not well understood. These are controlled in human physiology by a complex interplay of alloantigen distribution and presentation, cellular/humoral active and passive tolerance, hormones/chemokines/angiogenic factors and their gradients, systemic and local microbial communities. Reductive discrimination of these factors in physiology and pathology of model systems and humans requires simplification of the model and increased resolution of interrogative technologies. As a baseline, we have studied the gestational tissue dynamics in the syngeneic C57BL/6 mice, as the simplest immunological environment, and focused on validating the approach to increased data density and computational analysis pipeline afforded by highly polychromatic flow cytometry and machine learning interpretation. We mapped DC and T cell subsets, and comprehensively examined their maternal (decidual)-fetal (placental) interface dynamics. Both frequency and composition of decidual DCs changed across gestation, with a dramatic increase in myeloid DCs in early pregnancy, and exclusion of plasmacytoid DCs. CD4+ T cells, in contrast, were lower at all gestational ages and an unusual CD4-CD8-TCRαβ+group was prominent at mid-pregnancy. Dimensionality reduction with machine learning-aided clustering revealed that CD4-CD8- T cells were phenotypically different from CD4+ and CD8+ T cells. Additionally, divergence between maternal decidual and fetal placental compartment was prominent, with absence of DCs from the placenta, but not decidua or embryo. These results provide a novel framework and a syngeneic baseline on which the specific role of alloantigen/tolerance, polymicrobial environment, and models of pregnancy pathology can be precisely modeled and analyzed.

Dataset Information

Maternal CXCR4 deletion results in placental defects and pregnancy loss mediated by immune dysregulation.

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Maternal CXCR4 deletion results in placental defects and pregnancy loss mediated by immune dysregulation.

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