bims-reprim 2021-02-07 papers

Issue of 2021–02–07
five papers selected by
Iva Filipovic, Karolinska Institutet

medRxiv. 2021 Jan 26. pii: 2021.01.25.21250452. [Epub ahead of print]

SARS-CoV-2 infection in pregnancy is associated with robust inflammatory response at the maternal-fetal interface.

Pregnant women appear to be at increased risk for severe outcomes associated with COVID-19, but the pathophysiology underlying this increased morbidity and its potential impact on the developing fetus is not well understood. In this study of pregnant women with and without COVID-19, we assessed viral and immune dynamics at the placenta during maternal SARS-CoV-2 infection. Amongst uninfected women, ACE2 was detected by immunohistochemistry in syncytiotrophoblast cells of the normal placenta during early pregnancy but was rarely seen in healthy placentas at full term. Term placentas from women infected with SARS-CoV-2, however, displayed a significant increase in ACE2 levels. Using immortalized cell lines and primary isolated placental cells, we determined the vulnerability of various placental cell types to direct infection by SARS-CoV-2 in vitro . Yet, despite the susceptibility of placental cells to SARS-CoV-2 infection, viral RNA was detected in the placentas of only a subset (∼13%) of women in this cohort. Through single cell transcriptomic analyses, we found that the maternal-fetal interface of SARS-CoV-2-infected women exhibited markers associated with pregnancy complications, such as preeclampsia, and robust immune responses, including increased activation of placental NK and T cells and increased expression of interferon-related genes. Overall, this study suggests that SARS-CoV-2 is associated with immune activation at the maternal-fetal interface even in the absence of detectable local viral invasion. While this likely represents a protective mechanism shielding the placenta from infection, inflammatory changes in the placenta may also contribute to poor pregnancy outcomes and thus warrant further investigation.

DOI: https://doi.org/10.1101/2021.01.25.21250452

Proc Natl Acad Sci U S A. 2021 Feb 09. pii: e2013776118. [Epub ahead of print]118(6):

Macrophages inhibit and enhance endometriosis depending on their origin.

Chloe Hogg, Kavita Panir, Priya Dhami, Matthew Rosser, Matthias Mack, Daniel Soong, Jeffrey W Pollard, Stephen J Jenkins, Andrew W Horne, Erin Greaves.

Macrophages are intimately involved in the pathophysiology of endometriosis, a chronic inflammatory disorder characterized by the growth of endometrial-like tissue (lesions) outside the uterus. By combining genetic and pharmacological monocyte and macrophage depletion strategies we determined the ontogeny and function of macrophages in a mouse model of induced endometriosis. We demonstrate that lesion-resident macrophages are derived from eutopic endometrial tissue, infiltrating large peritoneal macrophages (LpM) and monocytes. Furthermore, we found endometriosis to trigger continuous recruitment of monocytes and expansion of CCR2+ LpM. Depletion of eutopic endometrial macrophages results in smaller endometriosis lesions, whereas constitutive inhibition of monocyte recruitment significantly reduces peritoneal macrophage populations and increases the number of lesions. Reprogramming the ontogeny of peritoneal macrophages such that embryo-derived LpM are replaced by monocyte-derived LpM decreases the number of lesions that develop. We propose a putative model whereby endometrial macrophages are "proendometriosis" while newly recruited monocyte-derived macrophages, possibly in LpM form, are "antiendometriosis." These observations highlight the importance of monocyte-derived macrophages in limiting disease progression.

Keywords: lesion; ontogeny; phenotype

DOI: https://doi.org/10.1073/pnas.2013776118

Front Immunol. 2020 ;11 607328

Macrophage Plasticity in Reproduction and Environmental Influences on Their Function.

Megan Chambers, April Rees, James G Cronin, Manju Nair, Nicholas Jones, Catherine A Thornton.

Macrophages are key components of the innate immune system and exhibit extensive plasticity and heterogeneity. They play a significant role in the non-pregnant cycling uterus and throughout gestation they contribute to various processes underpinning reproductive success including implantation, placentation and parturition. Macrophages are also present in breast milk and impart immunomodulatory benefits to the infant. For a healthy pregnancy, the maternal immune system must adapt to prevent fetal rejection and support development of the semi-allogenic fetus without compromising host defense. These functions are dependent on macrophage polarization which is governed by the local tissue microenvironmental milieu. Disruption of this microenvironment, possibly by environmental factors of infectious and non-infectious origin, can affect macrophage phenotype and function and is linked to adverse obstetric outcomes, e.g. spontaneous miscarriage and preterm birth. Determining environmental influences on cellular and molecular mechanisms that control macrophage polarization at the maternal-fetal interface and the role of this in pregnancy complications could support approaches to alleviating adverse pregnancy outcomes.

Keywords: air pollution; breast milk; immunometabolism; infection; macrophage plasticity; obesity; placenta; uterus

DOI: https://doi.org/10.3389/fimmu.2020.607328

J Reprod Immunol. 2021 Jan 27. pii: S0165-0378(21)00010-3. [Epub ahead of print]144 103280

Maternal platelets pass interstices of trophoblast columns and are not activated by HLA-G in early human pregnancy.

Jacqueline Guettler, Désirée Forstner, Gerhard Cvirn, Sabine Maninger, Beatrice A Brugger, Olivia Nonn, Nadja Kupper, Elisabeth Pritz, Stefan Wernitznig, Gottfried Dohr, Heinz Hutter, Herbert Juch, Berend Isermann, Shrey Kohli, Martin Gauster.

In early human gestation, maternal arterial blood flow into the intervillous space of the developing placenta is obstructed by invaded trophoblasts, which form cellular plugs in uterine spiral arteries. These trophoblast plugs have recently been described to be loosely cohesive with clear capillary-sized channels into the intervillous space by 7 weeks of gestation. Here, we analysed localisation of maternal platelets at the maternal-foetal interface of human first trimester pregnancy, and tested the hypothesis whether HLA-G, which is primarily expressed by extravillous trophoblasts, affects aggregation and adhesion of isolated platelets. Immunohistochemistry of first trimester placental sections localised maternal platelets in vessel-like channels and adjacent intercellular gaps of extravillous trophoblasts in distal parts of columns. Furthermore, this localisation was confirmed by transmission electron microscopy. Neither co-incubation of HLA-G overexpressing JAR cells with isolated platelets, nor incubation with cell-derived soluble HLA-G or recombinant HLA-G affected platelet adhesion and aggregation. Our study suggests that maternal platelets flow through vessel-like channels of distal trophoblast columns and spread into adjacent lateral intercellular gaps, where platelet-derived factors could contribute to trophoblast differentiation into the invasive phenotype.

Keywords: Development; Early pregnancy; HLA-G; Placenta; Platelets

DOI: https://doi.org/10.1016/j.jri.2021.103280

J Reprod Immunol. 2021 Jan 30. pii: S0165-0378(21)00013-9. [Epub ahead of print]144 103283

Interleukin-1 beta is significantly upregulated in the decidua of spontaneous and recurrent miscarriage placentas.

Sanja Löb, Niklas Amann, Christina Kuhn, Elisa Schmoeckel, Achim Wöckel, Alaleh Zati Zehni, Till Kaltofen, Simon Keckstein, Jan-Niclas Mumm, Sarah Meister, Thomas Kolben, Sven Mahner, Udo Jeschke, Theresa Vilsmaier.

BACKGROUND: Pregnancy is an extraordinarily complex immunological process. For successful pregnancy maintenance the maternal immune system must adapt to and tolerate the semi-allogenic fetus at the fetomaternal interface of the placenta. This balance is regulated by cytokines with a predominant T helper 2 (Th-2) system and a suppressed inflammatory T helper 1 (Th-1) response. This study investigates the role of the Th-1 pro-inflammatory cytokine Interleukin-1 beta (IL-1β) and its role in early pregnancy loss.
PATIENTS AND METHODS: In order to identify differences in IL- β levels a TaqMan® Human Cytokine Network Array, with placental tissue obtained from patients with healthy pregnancies (n = 15) and recurrent miscarriage (n = 15), was carried out. Protein expression of IL-1β in the decidua of healthy pregnancies (n = 15), spontaneous (n = 18) and recurrent miscarriages (n = 15), was investigated by immunohistochemistry. The identification of IL-1β expressing cells in the decidua was done with double-immunofluorescence.
RESULTS: Gene expression analysis identified a nearly 54-times higher expression of IL-1β in placental tissue of patients suffering from recurrent abortion. Immunohistochemistry confirmed a significant upregulation of IL-1β in the decidua of recurrent miscarriage specimens (p = 0.01) as well as in the decidua of women with spontaneous abortion (p = 0.001). Double-immunofluorescence identified decidual stoma cells as IL-1β expressing cells.
CONCLUSION: Significant upregulation of IL-1β may be associated with an imbalanced immune system and a procoagulant state that could be responsible for early pregnancy loss. These results provide new evidence of the complex interplay of IL-1β at the fetomaternal interface and its crucial role in miscarriage processes.

Keywords: First trimester placenta; Interleukin-1 beta; Recurrent miscarriage; Spontaneous miscarriage

DOI: https://doi.org/10.1016/j.jri.2021.103283