Inflammation-induced alterations in maternal-fetal Heme Oxygenase (HO) are associated with sustained innate immune cell dysregulation in mouse offspring.

Maide Ozen,Hui Zhao,Yang Yang,David K Stevenson,Lauren L Jantzie,Flora Kalish,Ronald J Wong,Leticia Reyes

doi:10.1371/journal.pone.0252642

Maide Ozen, Hui Zhao + Show 6 more

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https://doi.org/10.1371/journal.pone.0252642

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Abstract

Heme oxygenase-1 (HO-1) is an evolutionarily conserved stress response enzyme and important in pregnancy maintenance, fetal and neonatal outcomes, and a variety of pathologic conditions. Here, we investigated the effects of an exposure to systemic inflammation late in gestation [embryonic day (E)15.5] on wild-type (Wt) and HO-1 heterozygous (Het, HO-1+/-) mothers, fetuses, and offspring. We show that alterations in fetal liver and spleen HO homeostasis during inflammation late in gestation can lead to a sustained dysregulation of innate immune cell populations and intracellular myeloid HO-1 expression in the spleen through young adolescence [postnatal day 25] in mice.

Highlights

Normal pregnancy is an immunotolerant state [1]
We investigated whether an exposure to LPS90 results in fetoplacental inflammation and innate immune system reprogramming in the offspring at PN12 and PN25, which may have preceded our previously reported adaptive immune system changes using this model (Fig 1)
We have reported that placental vascular defects in pregnant Heme Oxygenase (HO)-1-deficient dams may be mediated by changes in angiogenesis and vasculogenesis, which might contribute to a low fetal survival rate and appear as an “apparent” infertility [12, 31]

Summary

Introduction

Normal pregnancy is an immunotolerant state [1]. Infection and/or inflammation during pregnancy can have devastating consequences for a mother, fetus, and newborn [1]. Adverse effects include the loss of maternal immunotolerance to the fetus, which can lead to spontaneous abortions, stillbirths, or preterm deliveries, as well as to a dysregulation of the fetal and neonatal immune systems and subsequent organ dysfunction [1, 2]. It is central to immune homeostasis [1, 2]. As such, it is evolutionarily conserved across many species [8, 9]. We have previously shown that a partial or total deficiency of HO-1

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