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      Placenta-derived IL-32β activates neutrophils to promote preeclampsia development

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          Abstract

          Immune activation at the maternal-fetal interface is a main pathogenic factor of preeclampsia (PE). Neutrophils (PMNs) are activated in PE patients, but the mechanism and consequences of PMN activation need to be further explored. Here, we demonstrated that interleukin-32 (IL-32) expression was significantly upregulated in syncytiotrophoblasts (STBs) and that IL-32β was the major isoform with increased expression in the placenta of severe PE (sPE) patients. Furthermore, the level of IL-32 expression in the placenta was correlated with its level in the serum of sPE patients, indicating that IL-32 in the serum is derived mainly from the placenta. Then, in vitro experiments showed that IL-32β could highly activate PMNs and that these IL-32β-activated PMNs were better able to adhere to endothelial cells (HUVECs) and enhance the expression of vascular cell adhesion molecule-1 (VCAM-1) and intercellular cell adhesion molecule-1 (ICAM-1) in HUVECs, which could be reversed by preincubation with the NADPH oxidase inhibitor VAS 2870. In addition, we showed that IL-32β mainly activated PMNs by binding to proteinase 3. Finally, IL-32β administration induced a PE-like phenotype in a pregnant mouse model. This study provides evidence of the involvement of IL-32β in the pathogenesis of PE.

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          Most cited references51

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          Pre-eclampsia.

          Pre-eclampsia remains a leading cause of maternal and perinatal mortality and morbidity. It is a pregnancy-specific disease characterised by de-novo development of concurrent hypertension and proteinuria, sometimes progressing into a multiorgan cluster of varying clinical features. Poor early placentation is especially associated with early onset disease. Predisposing cardiovascular or metabolic risks for endothelial dysfunction, as part of an exaggerated systemic inflammatory response, might dominate in the origins of late onset pre-eclampsia. Because the multifactorial pathogenesis of different pre-eclampsia phenotypes has not been fully elucidated, prevention and prediction are still not possible, and symptomatic clinical management should be mainly directed to prevent maternal morbidity (eg, eclampsia) and mortality. Expectant management of women with early onset disease to improve perinatal outcome should not preclude timely delivery-the only definitive cure. Pre-eclampsia foretells raised rates of cardiovascular and metabolic disease in later life, which could be reason for subsequent lifestyle education and intervention. Copyright 2010 Elsevier Ltd. All rights reserved.
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            Pre-eclampsia.

            Pre-eclampsia affects 3-5% of pregnancies and is traditionally diagnosed by the combined presentation of high blood pressure and proteinuria. New definitions also include maternal organ dysfunction, such as renal insufficiency, liver involvement, neurological or haematological complications, uteroplacental dysfunction, or fetal growth restriction. When left untreated, pre-eclampsia can be lethal, and in low-resource settings, this disorder is one of the main causes of maternal and child mortality. In the absence of curative treatment, the management of pre-eclampsia involves stabilisation of the mother and fetus, followed by delivery at an optimal time. Although algorithms to predict pre-eclampsia are promising, they have yet to become validated. Simple preventive measures, such as low-dose aspirin, calcium, and diet and lifestyle interventions, show potential but small benefit. Because pre-eclampsia predisposes mothers to cardiovascular disease later in life, pregnancy is also a window for future health. A collaborative approach to discovery and assessment of the available treatments will hasten our understanding of pre-eclampsia and is an effort much needed by the women and babies affected by its complications.
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              Phenotypic diversity and plasticity in circulating neutrophil subpopulations in cancer.

              Controversy surrounds neutrophil function in cancer because neutrophils were shown to provide both pro- and antitumor functions. We identified a heterogeneous subset of low-density neutrophils (LDNs) that appear transiently in self-resolving inflammation but accumulate continuously with cancer progression. LDNs display impaired neutrophil function and immunosuppressive properties, characteristics that are in stark contrast to those of mature, high-density neutrophils (HDNs). LDNs consist of both immature myeloid-derived suppressor cells (MDSCs) and mature cells that are derived from HDNs in a TGF-β-dependent mechanism. Our findings identify three distinct populations of circulating neutrophils and challenge the concept that mature neutrophils have limited plasticity. Furthermore, our findings provide a mechanistic explanation to mitigate the controversy surrounding neutrophil function in cancer.
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                Author and article information

                Contributors
                yayihou@nju.edu.cn
                yalihu@nju.edu.cn
                Journal
                Cell Mol Immunol
                Cell Mol Immunol
                Cellular and Molecular Immunology
                Nature Publishing Group UK (London )
                1672-7681
                2042-0226
                11 March 2021
                11 March 2021
                April 2021
                : 18
                : 4
                : 979-991
                Affiliations
                [1 ]GRID grid.428392.6, ISNI 0000 0004 1800 1685, Department of Obstetrics and Gynecology, , The Affiliated Drum Tower Hospital of Nanjing University Medical School, ; Nanjing, China
                [2 ]GRID grid.89957.3a, ISNI 0000 0000 9255 8984, Department of Obstetrics and Gynecology, , Drum Tower Clinic Medical College of Nanjing Medical University, ; Nanjing, Jiangsu China
                [3 ]GRID grid.41156.37, ISNI 0000 0001 2314 964X, The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, , Nanjing University, ; Nanjing, China
                Article
                636
                10.1038/s41423-021-00636-5
                8115232
                33707686
                43360aa8-eeba-4fef-978a-1c8720409a46
                © The Author(s) 2021

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 13 August 2020
                : 3 January 2021
                Funding
                Funded by: National Key R&D Program of China (2018YFC1004404),Jiangsu Provincial Key Medical Center (YXZXB2016004),Jiangsu Biobank of Clinical Resources (BM2015004)
                Funded by: FundRef https://doi.org/10.13039/501100002858, China Postdoctoral Science Foundation;
                Award ID: 2019M651807
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/501100001809, National Natural Science Foundation of China (National Science Foundation of China);
                Award ID: 81701474
                Award Recipient :
                Funded by: National Natural Science Foundation of China (82071600)
                Funded by: Maternal and Child Health Project in Jiangsu Province (F201742)
                Funded by: Key Research and Development Program of Jiangsu Province (BE2019706)
                Categories
                Article
                Custom metadata
                © The Author(s), under exclusive licence to CSI and USTC 2021

                Immunology
                il-32,neutrophil,preeclampsia,ros,huvec,cytokines,innate immune cells
                Immunology
                il-32, neutrophil, preeclampsia, ros, huvec, cytokines, innate immune cells

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