Prenatal inflammation perturbs murine fetal hematopoietic development and causes persistent changes to postnatal immunity

López, Diego A.; Apostol, April C.; Lebish, Eric J.; Valencia, Clint H.; Romero-Mulero, Mari Carmen; Pavlovich, Polina V.; Hernandez, Gloria; Forsberg, Erik; Cabezas-Wallscheid, Nina; Beaudin, Anna E.

doi:10.1016/j.celrep.2022.111677

Cited by 25 publications

(31 citation statements)

References 69 publications

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“…Indeed, IFNγ was highly upregulated in maternal serum in response to Pru infection. Although IL-1α and IL-1β were more significantly increased in the fetal liver as compared to IFNγ in response to infection, our previous transcriptional analysis of fetal HSPCs suggested that fetal HSPCs were not highly responsive to IL-1 signaling (López et al ., 2022).…”

Section: Discussionmentioning

confidence: 92%

“…Using a poly(I:C)-induced model of maternal immune activation (MIA), we have recently demonstrated that Type I interferon-mediated prenatal inflammation can drive lasting changes to postnatal immune function by specifically activating lymphoid-biased drHSCs (López et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

“…The copyright holder for this preprint this version posted November 29, 2022. ; https://doi.org/10.1101/2022.11.29.518417 doi: bioRxiv preprint Using a poly(I:C)-induced model of maternal immune activation (MIA), we have recently demonstrated that Type I interferon-mediated prenatal inflammation can drive lasting changes to postnatal immune function by specifically activating lymphoid-biased drHSCs (López et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

“…To investigate the fetal HSC response via the IFNγ receptor, IFNγ receptor knock out (IFNγRKO) mice (JAX 003288) were bred with wildtype C57BL/6J (WT) mice to generate mice with one copy of IFNγR (+/- mice). All saline controls were collected in parallel and published previously in (López et al ., 2022). Pregnant dams were euthanized, and fetuses were dissected from the uterine horn.…”

Section: Methodsmentioning

confidence: 99%

“…Transplantation assays were performed as recently described (López et al ., 2022). Briefly, FlkSwitch mice were used as donors for cell isolation and 8-to 12-week-old WT C57BL/6 were used as recipients.…”

Section: Methodsmentioning

confidence: 99%

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IFNγ and acute prenatal infection withToxoplasma gondiiactivate fetal hematopoietic stem cells

Apostol

Otsuka

López

et al. 2022

Preprint

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Infection in the adult organism drives cytokine-mediated inflammation that directly influences hematopoietic stem cell (HSC) function and differentiation within the bone marrow, but much less is known about the fetal hematopoietic response to maternal infection during pregnancy. Here, we investigated the fetal hematopoietic response to maternal infection with Toxoplasma gondii (T. gondii). T. gondii is an intracellular parasite that elicits Type II IFNγ-mediated maternal immunity to prevent vertical transmission and promote parasite clearance. The production of excessive IFNγ during maternal infection with T. gondii has dire consequences for the developing fetus, such as reduced birth weights and premature abortion, but the effects on developing hematopoietic cells and the signals that mediate these interactions have not been investigated. Our investigation reveals that the heterogenous fetal HSC pool responds to T. gondii infection with virulence-dependent changes in proliferation, self-renewal potential, and lineage output. We demonstrate that maternal IFNγ crosses the fetal-maternal interface and is perceived directly by fetal HSCs. By directly comparing the effects of maternal IFNγ injection with maternal T. gondii infection, our observations reveal that IFNγ mimics several aspects of the fetal HSC response to infection. Moreover, our data disentangle the role of additional infection-induced inflammatory cytokines in driving the expansion of independent downstream hematopoietic progenitors. Together, our findings illuminate the robust response of fetal hematopoietic stem cells to prenatal infection, and demonstrate that this response is distinct from the adult HSC response to IFNγ-induced inflammation.

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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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IFNγ and acute prenatal infection withToxoplasma gondiiactivate fetal hematopoietic stem cells

Apostol

Otsuka

López

et al. 2022

Preprint

Self Cite

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Beyond defence: Immune architects of ovarian health and disease

Bazzano,

Köninger,

Solano

2024

Semin Immunopathol

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Throughout the individual’s reproductive period of life the ovary undergoes continues changes, including cyclic processes of cell death, tissue regeneration, proliferation, and vascularization. Tissue-resident leucocytes particularly macrophages, play a crucial role in shaping ovarian function and maintaining homeostasis. Macrophages crucially promote angiogenesis in the follicles and corpora lutea, thereby supporting steroidogenesis. Recent research on macrophage origins and early tissue seeding has unveiled significant insights into their role in early organogenesis, e.g. in the testis. Here, we review evidence about the prenatal ovarian seeding of leucocytes, primarily macrophages with angiogenic profiles, and its connection to gametogenesis. In the prenatal ovary, germ cells proliferate, form cysts, and undergo changes that, following waves of apoptosis, give rice to the oocytes contained in primordial follicles. These follicles constitute the ovarian reserve that lasts throughout the female’s reproductive life. Simultaneously, yolk-sac-derived primitive macrophages colonizing the early ovary are gradually replaced or outnumbered by monocyte-derived fetal macrophages. However, the cues indicating how macrophage colonization and follicle assembly are related are elusive. Macrophages may contribute to organogenesis by promoting early vasculogenesis. Whether macrophages contribute to ovarian lymphangiogenesis or innervation is still unknown. Ovarian organogenesis and gametogenesis are vulnerable to prenatal insults, potentially programming dysfunction in later life, as observed in polycystic ovary syndrome. Experimental and, more sparsely, epidemiological evidence suggest that adverse stimuli during pregnancy can program defective folliculogenesis or a diminished follicle reserve in the offspring. While the ovary is highly sensitive to inflammation, the involvement of local immune responses in programming ovarian health and disease remains to be thoroughly investigated.

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The fetal programming effect of maternal immune activation (MIA) on the offspring’s immune system

Hofsink,

Groenink,

Plösch

2024

Semin Immunopathol

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The first 1000 days of life is a critical period of development in which adverse circumstances can have long-term consequences for the child’s health. Maternal immune activation is associated with increased risk of neurodevelopmental disorders in the child. Aberrant immune responses have been reported in individuals with neurodevelopmental disorders. Moreover, lasting effects of maternal immune activation on the offspring’s immune system have been reported. Taken together, this indicates that the effect of maternal immune activation is not limited to the central nervous system. Here, we explore the impact of maternal immune activation on the immune system of the offspring. We first describe the development of the immune system and provide an overview of reported alterations in the cytokine profiles, immune cell profiles, immune cell function, and immune induction in pre-clinical models. Additionally, we highlight recent research on the impact of maternal COVID-19 exposure on the neonatal immune system and the potential health consequences for the child. Our review shows that maternal immune activation alters the offspring’s immune system under certain conditions, but the reported effects are conflicting and inconsistent. In general, epigenetic modifications are considered the mechanism for fetal programming. The available data was insufficient to identify specific pathways that may contribute to immune programming. As a consequence of the COVID-19 pandemic, more research now focuses on the possible health effects of maternal immune activation on the offspring. Future research addressing the offspring’s immune response to maternal immune activation can elucidate specific pathways that contribute to fetal immune programming and the long-term health effects for the offspring.

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Prenatal inflammation perturbs murine fetal hematopoietic development and causes persistent changes to postnatal immunity

Cited by 25 publications

References 69 publications

IFNγ and acute prenatal infection withToxoplasma gondiiactivate fetal hematopoietic stem cells

IFNγ and acute prenatal infection withToxoplasma gondiiactivate fetal hematopoietic stem cells

Beyond defence: Immune architects of ovarian health and disease

The fetal programming effect of maternal immune activation (MIA) on the offspring’s immune system

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