bims-reprim 2021-01-17 papers

Issue of 2021–01–17
five papers selected by
Iva Filipovic, Karolinska Institutet

Science. 2021 01 15. 371(6526): 271-276

GPER1 is required to protect fetal health from maternal inflammation.

Alfred T Harding, Marisa A Goff, Heather M Froggatt, Jean K Lim, Nicholas S Heaton.

Type I interferon (IFN) signaling in fetal tissues causes developmental abnormalities and fetal demise. Although pathogens that infect fetal tissues can induce birth defects through the local production of type I IFN, it remains unknown why systemic IFN generated during maternal infections only rarely causes fetal developmental defects. Here, we report that activation of the guanine nucleotide-binding protein-coupled estrogen receptor 1 (GPER1) during pregnancy is both necessary and sufficient to suppress IFN signaling and does so disproportionately in reproductive and fetal tissues. Inactivation of GPER1 in mice halted fetal development and promoted fetal demise, but only in the context of maternal inflammation. Thus, GPER1 is a central regulator of IFN signaling during pregnancy that allows dynamic antiviral responses in maternal tissues while also preserving fetal health.

DOI: https://doi.org/10.1126/science.aba9001

J Clin Med. 2021 Jan 07. pii: E194. [Epub ahead of print]10(2):

Different Background: Natural Killer Cell Profiles in Secondary versus Primary Recurrent Pregnancy Loss.

Laura Strobel, Kilian Vomstein, Christiana Kyvelidou, Susanne Hofer-Tollinger, Katharina Feil, Ruben-Jeremias Kuon, Susanne Ebner, Jakob Troppmair, Bettina Toth.

(1) Background: Prior studies suggested a significant impact of previous live births on peripheral natural killer cells (pNK) in patients with recurrent pregnancy loss (RPL). Patients with primary RPL (pRPL, no live birth) showed higher numbers of pNK than secondary RPL patients (sRPL, ≥ 1 live birth). (2) Methods: To further determine immunological differences between RPL patients and controls, we analysed pNK subpopulations and activation markers in pRPL (n = 47), sRPL (n = 24) and controls with previous live birth (sCtrl, n = 25) and nullipara (pCtrl, n = 60) within a prospective study. Percentages and numbers of CD56dimCD16bright cells, subpopulations and activation markers (CD57+, CD62L+, NKG2D+, NKp46+) were measured in non-pregnant RPL patients and n = 85 controls (n = 60 pCtrl, n = 25 sCtrl) in the mid-luteal phase by flow cytometry. (3) Results: Compared to sRPL patients, sCtrls showed higher CD56+ and CD56dimCD16bright numbers. Further, sRPL patients showed lower numbers of CD56dimCD16brightNKG2D+ and CD56dimCD16brightNKp46+ than sCtrls. (4) Conclusion: We suggest a chronic immune stimulation leading to a lower NK-cell count in sRPL patients with a lower NK cytotoxicity. This underlines the necessity to investigate pNK subpopulations as well as pRPL and sRPL separately to delineate the immune alterations in RPL.

Keywords: NKG2D; NKp46; cytotoxicity; natural killer cells; recurrent pregnancy loss

DOI: https://doi.org/10.3390/jcm10020194

FASEB J. 2021 Feb;35(2): e21272

Protective role of IL33 signaling in negative pregnancy outcomes associated with lipopolysaccharide exposure.

Keisuke Kozai, Khursheed Iqbal, Ayelen Moreno-Irusta, Regan L Scott, Mikaela E Simon, Pramod Dhakal, Patrick E Fields, Michael J Soares.

Interleukin 33 (IL33) signaling has been implicated in the establishment and maintenance of pregnancy and in pregnancy disorders. The goal of this project was to evaluate the role of IL33 signaling in rat pregnancy. The rat possesses hemochorial placentation with deep intrauterine trophoblast invasion; features also characteristic of human placentation. We generated and characterized a germline mutant rat model for IL33 using CRISPR/Cas9 genome editing. IL33 deficient rats exhibited deficits in lung responses to an inflammatory stimulus (Sephadex G-200) and to estrogen-induced uterine eosinophilia. Female rats deficient in IL33 were fertile and exhibited pregnancy outcomes (gestation length and litter size) similar to wild-type rats. Placental weight was adversely affected by the disruption of IL33 signaling. A difference in pregnancy-dependent adaptations to lipopolysaccharide (LPS) exposure was observed between wild-type and IL33 deficient pregnancies. Pregnancy in wild-type rats treated with LPS did not differ significantly from pregnancy in vehicle-treated wild-type rats. In contrast, LPS treatment decreased fetal survival rate, fetal and placental weights, and increased fetal growth restriction in IL33 deficient rats. In summary, a new rat model for investigating IL33 signaling has been established. IL33 signaling participates in the regulation of placental development and protection against LPS-induced fetal and placental growth restriction.

Keywords: IL33; fetal growth restriction; lipopolysaccharide; placental development; pregnancy outcome

DOI: https://doi.org/10.1096/fj.202001782RR

J Reprod Immunol. 2021 Jan 02. pii: S0165-0378(20)30191-1. [Epub ahead of print]143 103270

Kynurenine promotes the cytotoxicity of NK cells through aryl hydrocarbon receptor in early pregnancy.

Shao-Liang Yang, Hai-Xia Tan, Tian-Tian Niu, Da-Jin Li, Hai-Yan Wang, Ming-Qing Li.

During early pregnancy, decidual NK (dNK) cells play indispensable roles in many processes including the decidualization, the implantation, and the maintenance of immune tolerance. Abnormal cytotoxic activity of NK cells can cause recurrent spontaneous abortion (RSA), while the regulatory mechanism of NK cytotoxicity remains to be unclear. In this study, we found that kynurenine in decidua and villus was in a comparable level between patients with RSA and normal pregnancy women. However, the aryl hydrocarbon receptor (AhR) in decidual NK cells was significantly increased in RSA. Compared with AhR- NK cells, cytotoxic activity-related molecules (NKP30, NKP46, NKG2D, perforin, granzyme B and IFN-γ) was highly expressed in both AhR+ peripheral and decidual NK cells, and kynurenine stimulation promoted the expression of killer receptors and the cytoplasmic granules in an AhR-dependent manner. Stimulation with TNF-α, IL-β and LPS upregulated the AhR expression in dNK cells in vitro. These results indicate that kyn/AhR signal enhances the cytotoxicity of NK cells, and increased expression of AhR may be an induction factor of RSA.

Keywords: Aryl hydrocarbon receptor; Kynurenine; NK cell; Pregnancy

DOI: https://doi.org/10.1016/j.jri.2020.103270

J Cell Mol Med. 2021 Jan 12.

A novel Cytochrome P450 26A1 expressing NK cell subset at the mouse maternal-foetal interface.

Dan-Ping Wei, Dan-Dan Li, Ai-Qin Gu, Wen-Heng Ji, Ying Yang, Jing-Pian Peng.

Cyp26a1 had important roles in mouse embryo implantation and was highly expressed in some of NK cells at the human maternal-foetal interface in early pregnancy. However, the regulatory effect of Cyp26a1 on NK cells remains poorly understood. Through qPCR and flow cytometric assays, we found that Cyp26a1 was expressed by mouse uterine NK cells but not spleen NK cells during the peri-implantation period and there was a group of NK cells that highly expressed Cyp26a1, that is Cyp26a1+ NK cell subset. single cell-population transcriptome sequencing on Cyp26a1+ NK and Cyp26a1- NK cell subsets was performed. We found that there were 3957 differentially expressed genes in the Cyp26a1+ NK cell subset with a cut-off of fold change ≥2 and FDR < 0.01, 2509 genes were up-regulated and 1448 genes were down-regulated in Cyp26a1+ NK cell subset. Moreover, cytokine-cytokine receptor interaction signalling pathway and natural killer cell-mediated cytotoxicity signalling pathway were enriched according to KEGG pathway enrichment analysis. We further found that the expression of Gzma and Klrg1 was significantly increased and Fcgr4 was significantly decreased when inhibiting Cyp26a1. Our experimental results show that there is a novel NK cell subset of Cyp26a1+ NK cells in mouse uterus and Cyp26a1 can regulate the gene expression of Gzma, Klrg1 and Fcgr4 in the Cyp26a1+ NK cells.

Keywords: Cyp26a1+NK cell; early pregnancy; maternal-foetal interface

DOI: https://doi.org/10.1111/jcmm.16285