Heme oxygenase-1 deficiency results in splenic T-cell dysregulation in offspring of mothers exposed to late gestational inflammation

Maide Ozen, Hui Zhao, Flora Kalish, Yang Yang, Ann Folkins, Irina Burd, Ronald J. Wong, David K. Stevenson

Research output: Contribution to journalArticle

Abstract

Problem: Infection during pregnancy can disrupt regulatory/effector immune system balance, resulting in adverse pregnancy and fetal-neonatal outcomes. Heme oxygenase-1 (HO-1) is a major regulatory enzyme in the immune system. We observed maternal immune response dysregulation during late gestational inflammation (LGI), which may be mediated by HO-1. Here, we extend these studies to examine the immune response of offspring. Method of study: Pregnant wild-type (Wt) and HO-1 heterozygote (Het) dams were treated with lipopolysaccharide (LPS) or vehicle at E15.5. Pups' splenic immune cells were characterized using flow cytometry. Results: CD3+CD4+CD25+ (Tregs) and CD3+CD8+ (Teffs) T cells in Wt and Het were similar in control neonates and increased with age. We showed not only age- but also genotype-specific and long-lasting T-cell dysregulation in pups after maternal LGI. The persistent immune dysregulation, mediated by HO-1 deficiency, was reflected as a decrease in Treg FoxP3 and CD3+CD8+ T cells, and an increase in CD4+/CD8+ T-cell and Treg/Teff ratios in Hets compared with Wt juvenile mice after maternal exposure to LGI. Conclusion: Maternal exposure to LGI can result in dysregulation of splenic T cells in offspring, especially in those with HO-1 deficiency. We speculate that these immune alterations are the basis of adverse outcomes in neonates from mothers exposed to low-grade (subclinical) infections.

Original languageEnglish (US)
JournalAmerican Journal of Reproductive Immunology
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Heme Oxygenase-1
Inflammation
T-Lymphocytes
Maternal Exposure
Heterozygote
Immune System
Eragrostis
Mothers
Pregnancy
Asymptomatic Infections
Lipopolysaccharides
Flow Cytometry
Genotype
Heme Oxygenase 1 Deficiency
Enzymes
Infection

Keywords

  • Heme oxygenase-1
  • Maternal inflammation
  • Neonatal immune response

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Reproductive Medicine
  • Obstetrics and Gynecology

Cite this

Heme oxygenase-1 deficiency results in splenic T-cell dysregulation in offspring of mothers exposed to late gestational inflammation. / Ozen, Maide; Zhao, Hui; Kalish, Flora; Yang, Yang; Folkins, Ann; Burd, Irina; Wong, Ronald J.; Stevenson, David K.

In: American Journal of Reproductive Immunology, 01.01.2018.

Research output: Contribution to journalArticle

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AU - Zhao, Hui

AU - Kalish, Flora

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AU - Folkins, Ann

AU - Burd, Irina

AU - Wong, Ronald J.

AU - Stevenson, David K.

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AB - Problem: Infection during pregnancy can disrupt regulatory/effector immune system balance, resulting in adverse pregnancy and fetal-neonatal outcomes. Heme oxygenase-1 (HO-1) is a major regulatory enzyme in the immune system. We observed maternal immune response dysregulation during late gestational inflammation (LGI), which may be mediated by HO-1. Here, we extend these studies to examine the immune response of offspring. Method of study: Pregnant wild-type (Wt) and HO-1 heterozygote (Het) dams were treated with lipopolysaccharide (LPS) or vehicle at E15.5. Pups' splenic immune cells were characterized using flow cytometry. Results: CD3+CD4+CD25+ (Tregs) and CD3+CD8+ (Teffs) T cells in Wt and Het were similar in control neonates and increased with age. We showed not only age- but also genotype-specific and long-lasting T-cell dysregulation in pups after maternal LGI. The persistent immune dysregulation, mediated by HO-1 deficiency, was reflected as a decrease in Treg FoxP3 and CD3+CD8+ T cells, and an increase in CD4+/CD8+ T-cell and Treg/Teff ratios in Hets compared with Wt juvenile mice after maternal exposure to LGI. Conclusion: Maternal exposure to LGI can result in dysregulation of splenic T cells in offspring, especially in those with HO-1 deficiency. We speculate that these immune alterations are the basis of adverse outcomes in neonates from mothers exposed to low-grade (subclinical) infections.

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