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Decidual macrophages contribute to the unique leukocyte composition at the fetal-maternal interface by production of IL-35, induction of Treg cells and production of homeostatic chemokines
Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
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2015 (English)Manuscript (preprint) (Other academic)
Abstract [en]

Reproductive success depends on the ability of the maternal immune system to adapt in order to tolerate and support the growing semi-allogenic fetus. Macrophages, being a major leukocyte population in the uterine mucosa (decidua), may play a central role in promoting the unique composition and regulatory phenotype of leukocytes that is characteristic for the fetal-maternal interface. We show that decidual macrophages display a predominantly immune regulatory gene profile and produce the immunosuppressive cytokine IL-35 but no other members of the IL-12 family (IL-12, IL-23 and IL-27). Decidual macrophages also promoted the selective expansion of CD25highFoxp3+ Tregs but not of Tbet+ Th1, GATA-3+ Th2 and Rorγt+ Th17 cells. In addition, these macrophages preferentially secreted the monocyte- and Treg-associated chemokines CCL2 and CCL18, while Th1-, Th2- and Th17-related chemokines were produced at low levels. Among in vitro macrophages, distinct chemokine profiles were observed; IL-4/13 upregulated Th2-associated chemokines (CCL17, CCL22, CCL26) while LPS/IFNγ upregulated Th1-associated chemokines (CXCL9, CXCL10, CXCL11, CCL5). M(IL-10) macrophages (induced by M-CSF and IL-10) showed a chemokine profile similar to that of decidual macrophages, as shown by gene expression and protein analysis. By using M(IL-10) macrophages as a model of decidual macrophages, we show that these cells promote the recruitment of CD14+ monocytes, while migration of several lymphocyte populations was unaltered or prevented. These data implicate decidual macrophages as critical regulators of the decidual leukocyte composition and phenotype that is associated with successful reproduction.

Place, publisher, year, edition, pages
2015.
National Category
Immunology Clinical Medicine
Identifiers
URN: urn:nbn:se:liu:diva-117182OAI: oai:DiVA.org:liu-117182DiVA: diva2:806730
Available from: 2015-04-21 Created: 2015-04-21 Last updated: 2016-03-23Bibliographically approved
In thesis
1. Immune regulation at the fetal‐maternal interface with focus on decidual macrophages
Open this publication in new window or tab >>Immune regulation at the fetal‐maternal interface with focus on decidual macrophages
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

A successful pregnancy requires that the maternal immune system adapts to tolerate the semi-allogeneic fetal-placental unit. This adaptation mainly occurs locally, i.e. at the fetal-maternal interface, where fetal-derived tissues come into close contact with maternal cells in the uterine endometrium (called decidua during pregnancy). Macrophages and regulatory T (Treg) cells are maternal immune cells that are enriched in the decidua and they likely play a central role in promoting fetal tolerance. However, the precise function of decidual macrophages and the factors regulating both macrophages and Treg cells in humans are unknown. The aim of this thesis was to characterize the phenotype and function of decidual macrophages from first trimester human pregnancy and to identify factors responsible for inducing tolerogenic properties in both decidual macrophages and Treg cells. CD14+ decidual macrophages showed characteristics of immune suppressive or homeostatic macrophages (expression of CD163, CD206 and CD209), mainly produced immunosuppressive cytokines, like IL-10 and IL-35, while levels of inflammatory cytokines, for instance IL-12 and IL-23, were low. Decidual macrophages also induced the expansion of CD25highFoxp3+ Treg cells, but not of Th1, Th2 and Th17 cells, in vitro. In addition, decidual macrophages preferentially secreted the monocyte- and Treg cell-associated chemokines CCL2 and CCL18, while Th1-, Th2- and Th17-related chemokines were produced at low levels. These results suggest that decidual macrophages contribute to create the unique decidual cell composition and a tolerogenic immune environment that is compatible with fetal development. Further, by comparing decidual macrophages with different in vitro macrophage subsets, we showed that M-CSF and IL-10, but not GM-CSF, Th1 or Th2 stimuli, induced macrophages that resemble decidual macrophages in terms of cell surface marker expression, cytokine andchemokine production and gene expression profile. First trimester placental tissue, in particular placental trophoblast cells, was identified as an important source of M-CSF and IL-10. We also demonstrated that human fetal-derived placental tissue can induce the characteristics of decidual macrophages (CD163+CD206+CD209+IL-10+CCL18+) and the selective expansion of functionally suppressive CD25highFoxp3+ Treg cells, the latter partly mediated through IL-10, TGF-β and TRAIL. The placenta also limited activation of Th cells, for instance by generally reduced cytokine production. Our data show that the placenta has a unique ability to induce tolerogenic immune cells with a reduced inflammatory potential, which is essential for maintaining tissue integrity and preventing inflammation-induced fetal loss.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2015. 150 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1448
National Category
Immunology Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-117183 (URN)10.3384/diss.diva-117183 (DOI)978-91-7519-117-1 (ISBN)
Public defence
2015-05-22, Linden, Campus US, Linköping, 13:00 (English)
Opponent
Supervisors
Available from: 2015-04-21 Created: 2015-04-21 Last updated: 2016-04-24Bibliographically approved

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Svensson Arvelund, JuditSöderberg, DanielWendel, CarolineFreland, SofiaBerg, GöranJenmalm, MariaErnerudh, Jan

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Svensson Arvelund, JuditSöderberg, DanielWendel, CarolineFreland, SofiaBerg, GöranJenmalm, MariaErnerudh, Jan
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Department of Clinical and Experimental MedicineFaculty of Health SciencesDivision of Drug ResearchDivision of Clinical SciencesFaculty of Medicine and Health SciencesDepartment of Gynaecology and Obstetrics in LinköpingDivision of Neuro and Inflammation ScienceDepartment of Clinical Immunology and Transfusion Medicine
ImmunologyClinical Medicine

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