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Macrophages at the fetal-maternal interface express markers of alternative activation and are induced by M-CSF and IL-10
Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
County Hospital Ryhov.
Helmholtz Centre Infect Research.
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2011 (English)In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 187, no 7, 3671-3682 p.Article in journal (Refereed) Published
Abstract [en]

During pregnancy, the maternal immune system is challenged by the presence of the fetus, which must be tolerated despite being semiallogeneic. Uterine mucosal (or decidual) macrophages (Mϕ), one of the major leukocyte populations at the fetal–maternal interface, have been implicated in fetal tolerance, but information regarding their regulation is scarce. In this study, we investigated the role of several factors potentially involved in the differentiation and polarization of decidual Mϕ with an in vitro Mϕ differentiation model. By using flow cytometry, we showed that M-CSF and IL-10 were potent inducers of M2 (immunoregulatory) Mϕ markers expressed on human decidual Mϕ (CD14, CD163, CD206, CD209). In contrast, proinflammatory stimuli, and unexpectedly also the Th2-associated IL-4 and IL-13, induced different patterns of expression, indicating that a Th2-dominated environment is not required for decidual Mϕ polarization. M-CSF/IL-10–stimulated and decidual Mϕ also showed similar cytokine secretion patterns, with production of IL-10 as well as IL-6, TNF, and CCL4. Conversely, the proinflammatory, LPS/IFN-γ–stimulated Mϕ produced significantly higher levels of TNF and no IL-10. We also used a gene array with 420 Mϕ-related genes, of which 100 were previously reported to be regulated in a global gene expression profiling of decidual Mϕ, confirming that M-CSF/IL-10–induced Mϕ are closely related to decidual Mϕ. Taken together, our results consistently point to a central role for M-CSF and in particular IL-10 in the shaping of decidual Mϕ with regulatory properties. These cytokines may therefore play an important role in supporting the homeostatic and tolerant immune milieu required for a successful pregnancy.

Place, publisher, year, edition, pages
American Association of Immunologists , 2011. Vol. 187, no 7, 3671-3682 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:liu:diva-73353DOI: 10.4049/jimmunol.1100130ISI: 000295036400026PubMedID: 21890660OAI: diva2:471340
Available from: 2012-01-02 Created: 2012-01-02 Last updated: 2015-04-21
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.
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1448
National Category
Immunology Clinical Medicine
urn:nbn:se:liu:diva-117183 (URN)10.3384/diss.diva-117183 (DOI)978-91-7519-117-1 (print) (ISBN)
Public defence
2015-05-22, Linden, Campus US, Linköping, 13:00 (English)
Available from: 2015-04-21 Created: 2015-04-21 Last updated: 2015-04-21Bibliographically approved

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Svensson, JuditJenmalm, MariaBerg, GöranErnerudh, Jan
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Clinical ImmunologyFaculty of Health SciencesPediatricsObstetrics and gynecologyDepartment of Gynecology and Obstetrics in LinköpingDepartment of Clinical Immunology and Transfusion Medicine
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