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      The effect of macrophage polarization on the expression of the oxytocin signalling system in enteric neurons

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          Abstract

          Background

          The aim of the current study was to investigate the effect of macrophage polarization on the expression of oxytocin (OT) and the oxytocin receptor (OTR) in enteric neurons.

          Methods

          In this study, we used a classic colitis model and D-mannose model to observe the correlation between macrophage polarization and OT signalling system. In order to further demonstrate the effect of macrophages, we examined the expression of OT signalling system after depletion of macrophages.

          Results

          The data showed that, in vitro, following polarization of macrophages to the M1 type by LPS, the macrophage supernatant contained proinflammatory cytokines (IL-1β, IL-6 and TNF-α) that inhibited the expression of OT and OTR in cultured enteric neurons; following macrophage polarization to the M2 type by IL4, the macrophage supernatant contained anti-inflammatory cytokines (TGF-β) that promoted the expression of OT and OTR in cultured enteric neurons. Furthermore, M1 macrophages decreased the expression of the OT signalling system mainly through STAT3/NF-κB pathways in cultured enteric neurons; M2 macrophages increased the expression of the OT signalling system mainly through activation of Smad2/3 and inhibition of the expression of Peg3 in cultured enteric neurons. In a colitis model, we demonstrated that macrophages were polarized to the M1 type during the inflammatory phase, with significant decreased in the expression of OT and OTR. When macrophages were polarized to the M2 type during the recovery phase, OT and OTR expression increased significantly. In addition, we found that D-mannose increased the expression of OT and OTR through polarization of macrophages to the M2 type.

          Conclusions

          This is the first study to demonstrate that macrophage polarization differentially regulates the expression of OT and OTR in enteric neurons.

          Supplementary Information

          The online version contains supplementary material available at 10.1186/s12974-021-02313-w.

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          Most cited references57

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          Alternative activation of macrophages: mechanism and functions.

          The concept of an alternative pathway of macrophage activation has stimulated interest in its definition, mechanism, and functional significance in homeostasis and disease. We assess recent research in this field, argue for a restricted definition, and explore pathways by which the T helper 2 (Th2) cell cytokines interleukin-4 (IL-4) and IL-13 mediate their effects on macrophage cell biology, their biosynthesis, and responses to a normal and pathological microenvironment. The stage is now set to gain deeper insights into the role of alternatively activated macrophages in immunobiology. Copyright 2010 Elsevier Inc. All rights reserved.
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            Transcriptional regulation of macrophage polarization: enabling diversity with identity.

            In terms of both phenotype and function, macrophages have remarkable heterogeneity, which reflects the specialization of tissue-resident macrophages in microenvironments as different as liver, brain and bone. Also, marked changes in the activity and gene expression programmes of macrophages can occur when they come into contact with invading microorganisms or injured tissues. Therefore, the macrophage lineage includes a remarkable diversity of cells with different functions and functional states that are specified by a complex interplay between microenvironmental signals and a hardwired differentiation programme that determines macrophage identity. In this Review, we summarize the current knowledge of transcriptional and chromatin-mediated control of macrophage polarization in physiology and disease.
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              The oxytocin receptor system: structure, function, and regulation.

              The neurohypophysial peptide oxytocin (OT) and OT-like hormones facilitate reproduction in all vertebrates at several levels. The major site of OT gene expression is the magnocellular neurons of the hypothalamic paraventricular and supraoptic nuclei. In response to a variety of stimuli such as suckling, parturition, or certain kinds of stress, the processed OT peptide is released from the posterior pituitary into the systemic circulation. Such stimuli also lead to an intranuclear release of OT. Moreover, oxytocinergic neurons display widespread projections throughout the central nervous system. However, OT is also synthesized in peripheral tissues, e.g., uterus, placenta, amnion, corpus luteum, testis, and heart. The OT receptor is a typical class I G protein-coupled receptor that is primarily coupled via G(q) proteins to phospholipase C-beta. The high-affinity receptor state requires both Mg(2+) and cholesterol, which probably function as allosteric modulators. The agonist-binding region of the receptor has been characterized by mutagenesis and molecular modeling and is different from the antagonist binding site. The function and physiological regulation of the OT system is strongly steroid dependent. However, this is, unexpectedly, only partially reflected by the promoter sequences in the OT receptor gene. The classical actions of OT are stimulation of uterine smooth muscle contraction during labor and milk ejection during lactation. While the essential role of OT for the milk let-down reflex has been confirmed in OT-deficient mice, OT's role in parturition is obviously more complex. Before the onset of labor, uterine sensitivity to OT markedly increases concomitant with a strong upregulation of OT receptors in the myometrium and, to a lesser extent, in the decidua where OT stimulates the release of PGF(2 alpha). Experiments with transgenic mice suggest that OT acts as a luteotrophic hormone opposing the luteolytic action of PGF(2 alpha). Thus, to initiate labor, it might be essential to generate sufficient PGF(2 alpha) to overcome the luteotrophic action of OT in late gestation. OT also plays an important role in many other reproduction-related functions, such as control of the estrous cycle length, follicle luteinization in the ovary, and ovarian steroidogenesis. In the male, OT is a potent stimulator of spontaneous erections in rats and is involved in ejaculation. OT receptors have also been identified in other tissues, including the kidney, heart, thymus, pancreas, and adipocytes. For example, in the rat, OT is a cardiovascular hormone acting in concert with atrial natriuretic peptide to induce natriuresis and kaliuresis. The central actions of OT range from the modulation of the neuroendocrine reflexes to the establishment of complex social and bonding behaviors related to the reproduction and care of the offspring. OT exerts potent antistress effects that may facilitate pair bonds. Overall, the regulation by gonadal and adrenal steroids is one of the most remarkable features of the OT system and is, unfortunately, the least understood. One has to conclude that the physiological regulation of the OT system will remain puzzling as long as the molecular mechanisms of genomic and nongenomic actions of steroids have not been clarified.
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                Author and article information

                Contributors
                liucy@sdu.edu.cn
                Journal
                J Neuroinflammation
                J Neuroinflammation
                Journal of Neuroinflammation
                BioMed Central (London )
                1742-2094
                8 November 2021
                8 November 2021
                2021
                : 18
                : 261
                Affiliations
                [1 ]GRID grid.27255.37, ISNI 0000 0004 1761 1174, Department of Physiology, School of Basic Medical Sciences, , Cheeloo Medical College, Shandong University, ; 44 Wenhua Xi Road, Jinan, 250012 Shandong People’s Republic of China
                [2 ]GRID grid.454761.5, ISNI 0000 0004 1759 9355, School of Biological Science and Technology, , Jinan University, ; 336 Nanxinzhuang Xi Road, Jinan, 250012 People’s Republic of China
                [3 ]GRID grid.452222.1, ISNI 0000 0004 4902 7837, Jinan Central Hospital Affiliated to Shandong University, ; Jinan, 250012 Shandong People’s Republic of China
                [4 ]GRID grid.27255.37, ISNI 0000 0004 1761 1174, Provincial Key Lab of Mental Disorders, , Shandong University, ; Jinan, 250012 Shandong People’s Republic of China
                Article
                2313
                10.1186/s12974-021-02313-w
                8573870
                34749758
                1c255b4d-7b73-41d0-b6f6-1bc233197747
                © The Author(s) 2021

                Open AccessThis 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                : 9 June 2021
                : 29 October 2021
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100012149, national key scientific instrument and equipment development projects of china;
                Award ID: NSFC31871160
                Award ID: 32071127
                Award Recipient :
                Categories
                Research
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                © The Author(s) 2021

                Neurosciences
                ot signalling system,macrophage polarization,proinflammatory and anti-inflammatory factors,neural-immune interactions

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