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Review
. 2023 Jun 19:14:1203719.
doi: 10.3389/fimmu.2023.1203719. eCollection 2023.

Energy metabolism and maternal-fetal tolerance working in decidualization

Xinhang Meng  1 , Chunqin Chen  1 , Jinfeng Qian  1 , Liyuan Cui  1 , Songcun Wang  1
Affiliations
Review

Energy metabolism and maternal-fetal tolerance working in decidualization

Xinhang Meng et al. Front Immunol. .

Abstract

One pivotal aspect of early pregnancy is decidualization. The decidualization process includes two components: the differentiation of endometrial stromal cells to decidual stromal cells (DSCs), as well as the recruitment and education of decidual immune cells (DICs). At the maternal-fetal interface, stromal cells undergo morphological and phenotypic changes and interact with trophoblasts and DICs to provide an appropriate decidual bed and tolerogenic immune environment to maintain the survival of the semi-allogeneic fetus without causing immunological rejection. Despite classic endocrine mechanism by 17 β-estradiol and progesterone, metabolic regulations do take part in this process according to recent studies. And based on our previous research in maternal-fetal crosstalk, in this review, we elaborate mechanisms of decidualization, with a special focus on DSC profiles from aspects of metabolism and maternal-fetal tolerance to provide some new insights into endometrial decidualization in early pregnancy.

Keywords: decidual immune cells; decidual stromal cells; decidualization; energy metabolism; maternal-fetal crosstalk; trophoblast cells.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Schematic mechanism of the energy metabolism during decidualization. (1) ATX-LPA-LPA3 signaling in the uterine epithelium induces decidualization via HB-EGF/COX-2-Bmp2/Wnt4 signaling pathways. Three subunits of the SPT holoenzyme (Sptlc1, Sptlc2, and Ssspta) are significantly up-regulated in mouse USCs, resulting in de novo synthesis of sphingolipids, to promote decidualization. (2) Glucose uptake is increased and is indispensable for decidualization by activating the histone modification status of the promoters of PRL, IGFBP1 and FOXO1. The FBP level in DSCs is significantly increased, which elevates IL-27 expression, triggering COX-2+ M2-like macrophages differentiation, Treg expansion, and Th2 bias to improve decidualization and trophoblast invasion. (3) cAMP enhances stromal cells proliferation through PKA/p-Creb/Ass1/L-Arg signaling pathway. Tryptophan enters into cells via SLC7A5 and stimulates the expression of PRL and IGFBP1 through kynurenine pathway. Accumulated α-KG derived from activated glutaminolysis contributes to ATP production and decidualization (4) The influences of carbohydrate metabolism, lipid metabolism and amino acid metabolism on DSC differentiation are not independent. For example, GPR120, receptor of ω-3 PUFAs, functions to promote decidualization by upregulating GLUT1-mediated glucose uptake and G6PD-mediated PPP of HEnSCs in a ERK1/2 and AMPK pathway. Endothelial-derived prostacyclin and PGE2 can accelerate decidualization by increasing intercellular cAMP in the endometrial perivascular stroma. ATX, autotaxin; LPA, lysophosphatidic acid; HB-EGF, heparin-binding epidermal growth factor; COX-2, cyclooxygenase-2; Bmp2, bone morphogenetic protein 2; SPT, serine palmitoyltransferase; USCs, uterine stromal cells; E2, estrogen; PRL, prolactin; IGFBP1, insulin growth factor binding protein 1; FOXO1, Forkhead box O1; FBP, fructose-1;6-bisphosphate; DSCs, decidual stromal cells; PFK1, phosphofructokinase 1; FBP1, fructose-bisphosphatase 1; Th, helper T cell; Treg, regulatory T cell; cAMP, cyclic adenosine monophosphate; PKA, protein kinase A; p-Creb, phosphorylated cAMP-response element binding protein; Ass1, Argininosuccinate synthase; Asl, Argininosuccinate lyase; L-Arg, L-Arginine; SLC7A5, solute carrier family 7; member 5; IDO, indoleamine 2;3-dioxygenase; AHR, Aryl hydrocarbon receptor; CYP1A1, Cytochrome P450 1A1; CYP1B1, Cytochrome P450 1B1; 2-OH E2, 2-hydroxy estradiol; 4-OH E2, 4-hydroxy estradiol; α-KG, α-ketoglutarate; Gln, glutamine; GLS1, glutaminase 1; Glu, Gln-glutamic acid; GLUD1, Glu dehydrogenase 1; GPT2, glutamic-pyruvic transaminase 2; GOT2, glutamic-oxaloacetic transaminase 2; GPR120, G-protein-coupled receptor 120; PUFA, Polyunsaturated fatty acids; GLUT1, glucose transporter-1; G6PD, glucose-6-phophate dehydrogenase; PPP, pentose-phosphate pathway; HEnSCs, human endometrial stromal cells; ERK1/2, extracellular regulated protein kinases; AMPK, adenosine 5’-monophosphate (AMP)-activated protein kinase; PGE2, prostaglandin E2; PGT, prostaglandin transporter.
Figure 2
Figure 2
The crosstalk of DSCs, trophoblasts and DICs during decidualization. During decidualization, high level of autophagy in DSCs upregulates TNFRSF14. The TNFSF14-TNFRSF14 signal contributes to the increased adhesion ability of DSCs by upregulating MMP9 expression, further facilitating the residence of dNKs in decidua. Moreover, DSCs increase the expression of CD56 on NK cells by producing abundant cAMP. CD56bright dNKs can promote vascular remodeling of trophoblast via VEGF-VEGFR2 interaction. DSCs also produce IL-33 to regulate decidualization by interacting with ST2+ DICs and promoting type 2 responses. EnSCs mediate maternal immune tolerance via ICAM, CXCL, ALCAM and gelatin signaling on CD8+T cells as well as NKG2D and CD137 on uNKs to inhibit their cytotoxicity. In addition to DSCs, EVT-secreted PFN1 promotes stromal cell decidualization via the down-regulation of ALOX5. Trophoblasts mediate the recruitment of iTregs, one of the important components of DICs, in a VIP/CCL5 pathway. Trophoblasts also promote the enrichment of FBP in DSCs, which can upregulate IL-27, further maintaining normal pregnancy by inducing decidual COX-2+ M2 macrophage differentiation. DSCs, decidual stromal cells; DICs, decidual immune cells; TNFSFR14, tumor necrosis factor (TNF) superfamily member receptor 14; TNFSF14, TNF superfamily member 14; MMP9, matrix metalloproteinase 9; dNKs, decidual natural killer cells; cAMP, cyclic adenosine monophosphate VEGF, vascular endothelial growth factor; VEGFR2, vascular endothelial growth factor receptor2; ICAM, intracellular adhesion molecule 1; CXCL, chemokine C-X-C motif ligand; ALCAM, activated leukocyte cell adhesion molecule; EVT, extracellular villus trophoblast; PFN1, profilin 1; ALOX5, lipoxygenase arachidonate 5-lipoxygenase.
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Grants and funding

This work was supported by grant from the Special Youth Project for Clinical Research in Health Industry of Shanghai Municipal Health Commission (20224Y0005 to SW), National Nature Science Foundation of China (NSFC) (82201852 to LYC, 82201855 to CC), and the Nature Science Foundation of Shanghai (21ZR1410500 to SW).

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