Cellular and molecular life sciences : CMLS, 2022-03, Vol.79 (3), p.173-173, Article 173
2022
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- Autor(en) / Beteiligte
- Titel
- An imbalance of the IL-33/ST2-AXL-efferocytosis axis induces pregnancy loss through metabolic reprogramming of decidual macrophages
- Ist Teil von
- Cellular and molecular life sciences : CMLS, 2022-03, Vol.79 (3), p.173-173, Article 173
- Ort / Verlag
- Cham: Springer International Publishing
- Erscheinungsjahr
- 2022
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- During embryo implantation, apoptosis is inevitable. These apoptotic cells (ACs) are removed by efferocytosis, in which macrophages are filled with a metabolite load nearly equal to the phagocyte itself. A timely question pertains to the relationship between efferocytosis-related metabolism and the immune behavior of decidual macrophages (dMΦs) and its effect on pregnancy outcome. Here, we report positive feedback of IL-33/ST2-AXL-efferocytosis leading to pregnancy failure through metabolic reprogramming of dMΦs. We compared the serum levels of IL-33 and sST2, along with IL-33 and ST2, efferocytosis and metabolism of dMΦs, from patients with normal pregnancies and unexplained recurrent pregnancy loss (RPL). We revealed disruption of the IL-33/ST2 axis, increased apoptotic cells and elevated efferocytosis of dMΦs from patients with RPL. The dMΦs that engulfed many apoptotic cells secreted more sST2 and less TGF-β, which polarized dMΦs toward the M1 phenotype. Moreover, the elevated sST2 biased the efferocytosis-related metabolism of RPL dMΦs toward oxidative phosphorylation and exacerbated the disruption of the IL-33/ST2 signaling pathway. Metabolic disorders also lead to dysfunction of efferocytosis, resulting in more uncleared apoptotic cells and secondary necrosis. We also screened the efferocytotic molecule AXL regulated by IL-33/ST2. This positive feedback axis of IL-33/ST2-AXL-efferocytosis led to pregnancy failure. IL-33 knockout mice demonstrated poor pregnancy outcomes, and exogenous supplementation with mouse IL-33 reduced the embryo losses. These findings highlight a new etiological mechanism whereby dMΦs leverage immunometabolism for homeostasis of the microenvironment at the maternal–fetal interface.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1420-682XeISSN: 1420-9071DOI: 10.1007/s00018-022-04197-2Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_11073329
- Format
- –
- Schlagworte
- Abortion, Spontaneous - immunology, Abortion, Spontaneous - pathology, Animals, Apoptosis, Axl protein, Axl Receptor Tyrosine Kinase, Biochemistry, Biomedical and Life Sciences, Biomedicine, Cell Biology, Decidua, Decidua - cytology, Disruption, Embryos, Etiology, Feedback, Female, Fetuses, Homeostasis, Humans, Implantation, Interleukin-1 Receptor-Like 1 Protein - blood, Interleukin-1 Receptor-Like 1 Protein - genetics, Interleukin-1 Receptor-Like 1 Protein - metabolism, Interleukin-33 - blood, Interleukin-33 - deficiency, Interleukin-33 - genetics, Interleukin-33 - metabolism, Life Sciences, Macrophages, Macrophages - cytology, Macrophages - metabolism, Membrane Potential, Mitochondrial - drug effects, Metabolic disorders, Metabolism, Metabolites, Mice, Mice, Inbred C57BL, Mice, Knockout, Microenvironments, Mitochondria - metabolism, Necrosis, Oligomycins - pharmacology, Original, Original Article, Oxidative Phosphorylation, Phenotypes, Phosphorylation, Positive feedback, Pregnancy, Protein Kinase Inhibitors - pharmacology, Proto-Oncogene Proteins - metabolism, Receptor Protein-Tyrosine Kinases - metabolism, Serum levels, Signal transduction, Signal Transduction - drug effects, Supplements