assessment-maternal-vascular-remodeling-during-pregnancy-mouse

Assessment of Maternal Vascular Remodeling During Pregnancy in the Mouse Uterus

The placenta mediates the exchange of factors such as gases and nutrients between mother and fetus and has specific demands for supply of blood from the ...

isolation-uterine-innate-lymphoid-cells-for-analysis-flow

Isolation of Uterine Innate Lymphoid Cells for Analysis by Flow Cytometry

Described here is a simple method to isolate and phenotype mouse group 1 uterine innate lymphoid cells (g1 uILCs) from individual pregnant uterus by flow ...

University of Cambridge

University of Cambridge School of Clinical Medicine

Mycobacterium tuberculosis infection is characterized by a strong inflammatory response whereby a few infected macrophages within the granuloma induce sustained cellular accumulation. The mechanisms coordinating this response are poorly characterized. We hypothesized that microparticles (MPs), which are submicron, plasma membrane-derived vesicles released by cells under both physiological and pathological conditions, are involved in this process. Aerosol infection of mice with M. tuberculosis increased CD45(+) MPs in the blood after 4 wk of infection, and in vitro infection of human and murine macrophages with mycobacteria enhanced MP release. MPs derived from mycobacteria-infected macrophages were proinflammatory, and when injected into uninfected mice they induced significant neutrophil, macrophage, and dendritic cell recruitment to the injection site. When incubated with naive macrophages, these MPs enhanced proinflammatory cytokine and chemokine release, and they aided in the disruption of the integrity of a respiratory epithelial cell monolayer, providing a mechanism for the egress of cells to the site of M. tuberculosis infection in the lung. In addition, MPs colocalized with the endocytic recycling marker Rab11a within macrophages, and this association increased when the MPs were isolated from mycobacteria-infected cells. M. tuberculosis-derived MPs also carried mycobacterial Ag and were able to activate M. tuberculosis-specific CD4(+) T cells in vivo and in vitro in a dendritic cell-dependent manner. Collectively, these data identify an unrecognized role for MPs in host response against M. tuberculosis by promoting inflammation, intercellular communication, and cell migration.

Microparticles from mycobacteria-infected macrophages promote inflammation and cellular migration.

NK cells express variable receptors that engage polymorphic MHC class I molecules and regulate their function. Maternal NK cells accumulate at the maternal-fetal interface and can interact with MHC class I molecules from both parents. The relative contribution of the two sets of parental MHC molecules to uterine NK cell function is unknown. Here we show that, in mice, maternal and not paternal MHC educates uterine NK cells to mature and acquire functional competence. The presence of an additional MHC allele that binds more inhibitory than activating NK cell receptors results in suppressed NK cell function, compromised uterine arterial remodelling and reduced fetal growth. Notably, reduced fetal growth occurs irrespectively of the parental origin of the inhibitory MHC. This provides biological evidence for the impact of MHC-dependent NK inhibition as a risk factor for human pregnancy-related complications associated with impaired arterial remodelling.

MHC-dependent inhibition of uterine NK cells impedes fetal growth and decidual vascular remodelling.

Much research in reproductive immunology is preoccupied with maternal tolerance of the semi-allogeneic fetus. This inevitably leads to the assumption that the maternal immune system should be suppressed, similarly to the immunosuppression needed to avoid rejection of an allograft. However, the parallels with transplantation immunology are misleading, and we discuss how interactions between variable immune system genes expressed on maternal natural killer (NK) cells and on the fetal trophoblast modulate fetal growth. Exaggerated suppression or activation of maternal NK cells associates with both extremes of birth weight.

Maternal uterine natural killer cells nurture fetal growth: in medio stat virtus.

Innate lymphoid cells (ILCs), including NK cells, contribute to barrier immunity and tissue homeostasis. In addition to the role of uterine NK cells in placentation and fetal growth, other uterine ILCs (uILCs) are likely to play roles in uterine physiology and pathology. In this article, we report on the composition of uILCs in the endometrium during the luteal phase and in the decidua during early pregnancy. Whereas nonkiller uILC1s and uILC2s are barely detectable in mouse and not detected in humans, a sizeable population of uILC3s is found in human endometrium and decidua, which are mostly NCR(+) and partially overlap with previously described IL-22-producing uterine NK cells. Development of mouse uILC3 is Nfil3 independent, suggesting unique features of uILCs. Indeed, although the cytokine production profile of mouse uILCs recapitulates that described in other tissues, IL-5, IL-17, and IL-22 are constitutively produced by uILC2s and uILC3s. This study lays the foundation to understand how ILCs function in the specialized uterine mucosa, both in tissue homeostasis and barrier immunity and during pregnancy.

Composition, Development, and Function of Uterine Innate Lymphoid Cells.

Maternal immune cells are an integral part of reproduction, but how they might cause pregnancy complications remains elusive. Macrophages and their dual function in inflammation and tissue repair are thought to play key yet undefined roles. Altered perinatal growth underpins adult morbidity, and natural killer (NK) cells may sustain fetal growth by establishing the placental blood supply. Using a mouse model of genetic inactivation of PI3K p110δ, a key intracellular signaling molecule in leukocytes, we show that p110δ regulates macrophage dynamics and NK-cell-mediated arterial remodeling. The uterus of dams with inactive p110δ had decreased IFN-γ and MHC class II(low) macrophages but enhanced IL-6. Poor vascular remodeling and a pro-inflammatory uterine milieu resulted in fetal death or growth retardation. Our results provide one mechanism that explains how imbalanced adaptations of maternal innate immune cells to gestation affect offspring well-being with consequence perinatally and possibly into adulthood. 

Disrupted PI3K p110δ Signaling Dysregulates Maternal Immune Cells and Increases Fetal Mortality In Mice.

Uterine NK cells are innate lymphoid cells (ILC) that populate the uterus and expand during pregnancy, regulating placental development and fetal growth in humans and mice. We have recently characterized the composition of uterine ILCs (uILCs), some of which require the transcription factor NFIL3, but the extent to which NFIL3-dependent cells support successful reproduction in mice is unknown. By mating Nfil3 (-/-) females with wild-type males, here we show the effects of NFIL3 deficiency in maternal cells on both the changes in uILCs during pregnancy and the downstream consequences on reproduction. Despite the presence of CD49a(+)Eomes(-) uILC1s and the considerable expansion of residual CD49a(+)Eomes(+) tissue-resident NK cells and uILC3s in pregnant Nfil3 (-/-) mice, we found incomplete remodeling of uterine arteries and decidua, placental defects, and fetal growth restriction in litters of normal size. These results show that maternal NFIL3 mediates non-redundant functions in mouse reproduction. 

The Residual Innate Lymphoid Cells in NFIL3-Deficient Mice Support Suboptimal Maternal Adaptations to Pregnancy.

Mammalian reproductive performance declines rapidly with advanced maternal age. This effect is largely attributed to the exponential increase in chromosome segregation errors in the oocyte with age. Yet many pregnancy complications and birth defects that become more frequent in older mothers, in both humans and mice, occur in the absence of karyotypic abnormalities. Here, we report that abnormal embryonic development in aged female mice is associated with severe placentation defects, which result from major deficits in the decidualisation response of the uterine stroma. This problem is rooted in a blunted hormonal responsiveness of the ageing uterus. Importantly, a young uterine environment can restore normal placental as well as embryonic development. Our data highlight the pivotal, albeit under-appreciated, impact of maternal age on uterine adaptability to pregnancy as major contributor to the decline in reproductive success in older females.Advanced maternal age has been associated with lower reproductive success and higher risk of pregnancy complications. Here the authors show that maternal ageing-related embryonic abnormalities in mouse are caused by decidualisation and placentation defects that can be rescued by transferring the embryo from an old to a young uterus.

Decidualisation and placentation defects are a major cause of age-related reproductive decline.

Throughout pregnancy, the placenta dynamically changes as trophoblast progenitors differentiate into mature trophoblast cell subtypes. This process is in part controlled by epigenetic regulation of DNA methylation leading to the inactivation of 'progenitor cell' genes and the activation of 'differentiation' genes. TET methylcytosine dioxygenases convert 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC) during DNA demethylation events. Here, we determine the spatiotemporal expression of TET1, TET2, and TET3 in specific trophoblast cell populations of mouse and human placentas throughout gestation, and consider their role in trophoblast cell differentiation and function.

ArticleTotal : 2	Year
Publication title Cited by 27	2015
Publication title Cited by 5	2021

Article	Year
Microparticles from mycobacteria-infected macrophages promote inflammation and cellular migration. Journal of immunology (Baltimore, Md. : 1950)\| PubMed ID: 23241892	2013
MHC-dependent inhibition of uterine NK cells impedes fetal growth and decidual vascular remodelling. Nature communications\| PubMed ID: 24577131	2014
Maternal uterine natural killer cells nurture fetal growth: in medio stat virtus. Trends in molecular medicine\| PubMed ID: 25618773	2015
Composition, Development, and Function of Uterine Innate Lymphoid Cells. Journal of immunology (Baltimore, Md. : 1950)\| PubMed ID: 26371244	2015
Disrupted PI3K p110δ Signaling Dysregulates Maternal Immune Cells and Increases Fetal Mortality In Mice. Cell reports\| PubMed ID: 26711346	2015
The Residual Innate Lymphoid Cells in NFIL3-Deficient Mice Support Suboptimal Maternal Adaptations to Pregnancy. Frontiers in immunology\| PubMed ID: 26925058	2016
Decidualisation and placentation defects are a major cause of age-related reproductive decline. Nature communications\| PubMed ID: 28874785	2017
Dynamic expression of TET1, TET2, and TET3 dioxygenases in mouse and human placentas throughout gestation. Placenta\| PubMed ID: 29108636	2017

Jens Kieckbusch

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