Warburg-like Glycolysis and Lactate Shuttle in Mouse Decidua during Early Pregnancy

Zuo, Ru-Juan; Gu, Xu; Qi, Qian-Rong; Wang, Tong-Song; Zhao, Xu-Yu; Liu, Ji‐Long; Yang, Zeng‐Ming

doi:10.1074/jbc.m115.656629

Cited by 94 publications

(91 citation statements)

References 40 publications

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“…In response to LA treatment, HIF-1α expression was elevated in mast cells, as predicted by previous studies (19, 38, 39). A known molecule targeted by HIF-1α in other systems is miR-155, which is pro-inflammatory in many lineages (41).…”

Section: Discussionsupporting

confidence: 87%

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Lactic Acid Suppresses IL-33–Mediated Mast Cell Inflammatory Responses via Hypoxia-Inducible Factor-1α–Dependent miR-155 Suppression

Abebayehu

Spence

Qayum

et al. 2016

The Journal of Immunology

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Lactic acid (LA) is present in tumors, asthma, and wound healing, environments with elevated IL-33 and mast cell infiltration. While IL-33 is a potent mast cell activator, how LA affects IL-33-mediated mast cell function is unknown. To investigate this, mouse bone marrow-derived mast cells (BMMC) were cultured with or without LA and activated with IL-33. LA reduced IL-33-mediated cytokine and chemokine production. Using inhibitors for monocarboxylate transporters (MCT) or replacing LA with sodium lactate revealed that LA effects are MCT-1- and pH-dependent. LA selectively altered IL-33 signaling, suppressing TAK1, JNK, ERK, and NFκB phosphorylation, but not p38 phosphorylation. LA effects in other contexts have been linked to HIF-1α, which was enhanced in BMMC treated with LA. Since HIF-1α has been shown to regulate the microRNA miR-155 in other systems, LA effects on miR-155-5p and -3p species were measured. In fact, LA selectively suppressed miR-155-5p in a HIF-1α-dependent manner. Moreover, overexpressing miR-155-5p, but not miR-155-3p, abolished LA effects on IL-33-induced cytokine production. These in vitro effects of reducing cytokines were consistent in vivo, since LA injected intraperitoneally into C57BL/6 mice suppressed IL-33-induced plasma cytokine levels. Lastly, IL-33 effects on primary human mast cells were suppressed by LA in an MCT-dependent manner. Our data demonstrate that LA, present in inflammatory and malignant microenvironments, can alter mast cell behavior to suppress inflammation.

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Section: Discussionsupporting

confidence: 87%

“…Since LA is known to promote HIF-1α production (19, 38, 39) and HIF-1α can control miR-155 expression (40–42), we hypothesized that LA-induced HIF-1α might suppress miR-155, yielding a net negative effect on IL-33 signaling. After 6 hours of LA treatment, HIF-1α mRNA increased nearly 3-fold, while miR-155-5p was suppressed >50% in BMMC.…”

Section: Resultsmentioning

confidence: 99%

Lactic Acid Suppresses IL-33–Mediated Mast Cell Inflammatory Responses via Hypoxia-Inducible Factor-1α–Dependent miR-155 Suppression

Abebayehu

Spence

Qayum

et al. 2016

The Journal of Immunology

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“…Interestingly, our analysis reveals that uterine, not liver resident g1 ILC upregulate Slc16a13 , which encodes lactate and pyruvate cell exporter MCT13 (Halestrap, 2013). Warburg-like glycolysis is indeed important for decidual development (Zuo et al 2015) and trNKs and ILC1s may provide lactate for the development of undifferentiated stromal cells in addition to other sources which function through other MCTs (MCT4). It is also tempting to hypothesise that uterine resident g1 ILCs produce lactate as a signal for arterial remodelling, in a manner analogous to how it signals for angiogenesis through acidosis in the tumour microenvironment (Romero-Garcia et al 2016).…”

Section: Discussionmentioning

confidence: 99%

Molecular definition of group 1 innate lymphoid cells in the mouse uterus

Filipovic

Chiossone

Vacca

et al. 2018

Preprint

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Determining the function of uterine lymphocytes is challenging because of the rapidly changing nature of the organ in response to sex hormones and, during pregnancy, to the invading fetal trophoblast cells. Here we provide the first genome-wide transcriptome atlas of mouse uterine group 1 innate lymphoid cells (g1 ILCs) at mid-gestation. The composition of g1 ILCs fluctuates throughout reproductive life, with Eomes-veCD49a+ ILC1s dominating before puberty and specifically expanding in second pregnancies, when the expression of CXCR6, a marker of memory cells, is upregulated. Tissue-resident Eomes+CD49a+ NK cells (trNK), which resemble human uterine NK cells, are most abundant during early pregnancy, and showcase gene signatures of responsiveness to TGF-β, connections with trophoblast, epithelial, endothelial and smooth muscle cells, leucocytes, as well as extracellular matrix. Unexpectedly, trNK cells express genes involved in anaerobic glycolysis, lipid metabolism, iron transport, protein ubiquitination, and recognition of microbial molecular patterns. Conventional NK cells expand late in gestation and may engage in crosstalk with trNK cells involving IL-18 and IFN-γ. These results identify trNK cells as the cellular hub of uterine g1 ILCs at mid-gestation and mark CXCR6+ ILC1s as potential memory cells of pregnancy.

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“…Indeed, Xiao et al (75) showed that the acidification of mouse uterus tissue was associated with early uterine preparation for embryo implantation. Therefore, lactic acid may play an important role in regulating acidification of the uterus for the implantation of the embryo (76).…”

Section: Blastocystsmentioning

confidence: 99%

Lactic Acid: A Novel Signaling Molecule in Early Pregnancy?

Huang

Muyayalo

et al. 2020

Front. Immunol.

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Aerobic glycolysis is a recognized feature shared by tumors, leading to the accumulation of lactic acid in their local microenvironments. Like the tumors, the blastocysts, placenta, trophoblasts and decidual immune cells can also produce a large amount of lactic acid through aerobic glycolysis during the early pregnancy. Moreover, the placenta expresses the transporters of the lactic acid. While several studies have described the role of lactic acid in the tumor microenvironment, especially lactic acid's modulation of immune cells, the role of lactic acid produced during pregnancy is still unclear. In this paper, we reviewed the scientific evidence detailing the effects of lactic acid in the tumor microenvironment. Based on the influence of the lactic acid on immune cells and tumors, we proposed that lactic acid released in the unique uterine environment could have similar effects on the trophoblast cells and immune cells during the early pregnancy.

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Warburg-like Glycolysis and Lactate Shuttle in Mouse Decidua during Early Pregnancy

Cited by 94 publications

References 40 publications

Lactic Acid Suppresses IL-33–Mediated Mast Cell Inflammatory Responses via Hypoxia-Inducible Factor-1α–Dependent miR-155 Suppression

Lactic Acid Suppresses IL-33–Mediated Mast Cell Inflammatory Responses via Hypoxia-Inducible Factor-1α–Dependent miR-155 Suppression

Molecular definition of group 1 innate lymphoid cells in the mouse uterus

Lactic Acid: A Novel Signaling Molecule in Early Pregnancy?

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