Blockage of heme oxygenase-1 abrogates the protective effect of regulatory T cells on murine pregnancy and promotes the maturation of dendritic cells

Anne Schumacher; Paul Ojiambo Wafula; Ana Teles; Tarek El-Mousleh; Nadja Linzke; Maria Laura Zenclussen; Stefanie Langwisch; Kristina Heinze; Ivonne Wollenberg; Pablo Ariel Casalis; Hans-Dieter Volk; Stefan Fest; Ana Claudia Zenclussen

doi:10.1371/journal.pone.0042301

Blockage of heme oxygenase-1 abrogates the protective effect of regulatory T cells on murine pregnancy and promotes the maturation of dendritic cells

PLoS One. 2012;7(8):e42301. doi: 10.1371/journal.pone.0042301. Epub 2012 Aug 10.

Authors

Anne Schumacher¹, Paul Ojiambo Wafula, Ana Teles, Tarek El-Mousleh, Nadja Linzke, Maria Laura Zenclussen, Stefanie Langwisch, Kristina Heinze, Ivonne Wollenberg, Pablo Ariel Casalis, Hans-Dieter Volk, Stefan Fest, Ana Claudia Zenclussen

Affiliation

¹ Department of Experimental Obstetrics and Gynaecology, Medical Faculty, Otto-von Guericke University of Magdeburg, Magdeburg, Germany.

Abstract

Regulatory T cells (Treg) play an important role in fetal protection. They expand during normal pregnancy and protect fetal antigens from maternal effector cells. Their effect is associated with the up-regulation of tolerance-associated molecules at the fetal-maternal interface. Among these, Heme Oxygenase-1 (HO-1, coded by Hmox1) is of special importance as its blockage correlates with increased abortion rates and its up-regulation positively affects pregnancy outcome. Here, we aimed to investigate whether the protective effect of Treg is mediated by HO-1 in a mouse model. HO-1 blockage by Zinc Protoporhyrin (ZnPPIX) abrogated the protective effect of Treg transfer. We found that HO-1 is important in maintaining maternal dendritic cells (DCs) in an immature state, which contributes to the expansion of the peripheral Treg population. This brings to light one essential pathway through which Treg mediates the semi-allogeneic fetus tolerance.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Abortion, Spontaneous / genetics
Abortion, Spontaneous / immunology
Abortion, Spontaneous / metabolism
Animals
Cytokines / immunology
Cytokines / metabolism
Dendritic Cells / immunology*
Dendritic Cells / metabolism*
Disease Models, Animal
Enzyme Inhibitors / pharmacology*
Female
Fetal Death / genetics
Fetal Death / immunology
Fetal Death / metabolism
Forkhead Transcription Factors / genetics
Forkhead Transcription Factors / metabolism
Gene Expression Regulation / drug effects
Heme Oxygenase-1 / antagonists & inhibitors*
Heme Oxygenase-1 / genetics
Heme Oxygenase-1 / metabolism
Immune Tolerance / genetics
Immune Tolerance / immunology
Inflammation Mediators / immunology
Inflammation Mediators / metabolism
Lymphocyte Activation / immunology
Male
Mice
Mice, Transgenic
Pregnancy
Pregnancy Outcome / genetics
Protoporphyrins / pharmacology*
T-Lymphocytes, Regulatory / drug effects
T-Lymphocytes, Regulatory / immunology*
T-Lymphocytes, Regulatory / metabolism*

Substances

Cytokines
Enzyme Inhibitors
Forkhead Transcription Factors
Foxp3 protein, mouse
Inflammation Mediators
Protoporphyrins
zinc protoporphyrin
Heme Oxygenase-1

Grants and funding

The present study was supported by grants from the German Research Association to ACZ (DFG ZE-526/4-1 and 526/5-1) and to SF (DFG FE 914/2-1). POW was funded by a PhD grant from the German Academic Exchange Program (DAAD) and Ana Teles is a grantee from the FCT foundation, Portugal. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.