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Theranostics 2021Tissue regeneration following injury from disease or medical treatment still represents a challenge in regeneration medicine. Prostaglandin E2 (PGE2), which involves... (Review)
Review
Tissue regeneration following injury from disease or medical treatment still represents a challenge in regeneration medicine. Prostaglandin E2 (PGE2), which involves diverse physiological processes via E-type prostanoid (EP) receptor family, favors the regeneration of various organ systems following injury for its capabilities such as activation of endogenous stem cells, immune regulation, and angiogenesis. Understanding how PGE2 modulates tissue regeneration and then exploring how to elevate the regenerative efficiency of PGE2 will provide key insights into the tissue repair and regeneration processes by PGE2. In this review, we summarized the application of PGE2 to guide the regeneration of different tissues, including skin, heart, liver, kidney, intestine, bone, skeletal muscle, and hematopoietic stem cell regeneration. Moreover, we introduced PGE2-based therapeutic strategies to accelerate the recovery of impaired tissue or organs, including 15-hydroxyprostaglandin dehydrogenase (15-PGDH) inhibitors boosting endogenous PGE2 levels and biomaterial scaffolds to control PGE2 release.
Topics: Animals; Dinoprostone; Humans; Regeneration; Signal Transduction; Wound Healing
PubMed: 34522214
DOI: 10.7150/thno.63396 -
Cell Research Jun 2022Lgr5 intestinal stem cells (ISCs) reside within specialized niches at the crypt base and harbor self-renewal and differentiation capacities. ISCs in the crypt base are...
Lgr5 intestinal stem cells (ISCs) reside within specialized niches at the crypt base and harbor self-renewal and differentiation capacities. ISCs in the crypt base are sustained by their surrounding niche for precise modulation of self-renewal and differentiation. However, how intestinal cells in the crypt niche and microbiota in enteric cavity coordinately regulate ISC stemness remains unclear. Here, we show that ISCs are regulated by microbiota and niche enteric serotonergic neurons. The gut microbiota metabolite valeric acid promotes Tph2 expression in enteric serotonergic neurons via blocking the recruitment of the NuRD complex onto Tph2 promoter. 5-hydroxytryptamine (5-HT) in turn activates PGE2 production in a PGE2 macrophage subset through its receptors HTR2A/3 A; and PGE2 via binding its receptors EP1/EP4, promotes Wnt/β-catenin signaling in ISCs to promote their self-renewal. Our findings illustrate a complex crosstalk among microbiota, intestinal nerve cells, intestinal immune cells and ISCs, revealing a new layer of ISC regulation by niche cells and microbiota.
Topics: Cell Self Renewal; Dinoprostone; Gastrointestinal Microbiome; Intestinal Mucosa; Intestines; Macrophages; Serotonergic Neurons; Stem Cells
PubMed: 35379903
DOI: 10.1038/s41422-022-00645-7 -
Proceedings of the National Academy of... Jun 2020IgG antibodies cause inflammation and organ damage in autoimmune diseases such as systemic lupus erythematosus (SLE). We investigated the metabolic profile of...
IgG antibodies cause inflammation and organ damage in autoimmune diseases such as systemic lupus erythematosus (SLE). We investigated the metabolic profile of macrophages isolated from inflamed tissues in immune complex (IC)-associated diseases, including SLE and rheumatoid arthritis, and following IgG Fcγ receptor cross-linking. We found that human and mouse macrophages undergo a switch to glycolysis in response to IgG IC stimulation, mirroring macrophage metabolic changes in inflamed tissue in vivo. This metabolic reprogramming was required to generate a number of proinflammatory mediators, including IL-1β, and was dependent on mTOR and hypoxia-inducible factor (HIF)1α. Inhibition of glycolysis, or genetic depletion of HIF1α, attenuated IgG IC-induced activation of macrophages in vitro, including primary human kidney macrophages. In vivo, glycolysis inhibition led to a reduction in kidney macrophage IL-1β and reduced neutrophil recruitment in a murine model of antibody-mediated nephritis. Together, our data reveal the molecular mechanisms underpinning FcγR-mediated metabolic reprogramming in macrophages and suggest a therapeutic strategy for autoantibody-induced inflammation, including lupus nephritis.
Topics: Animals; Cells, Cultured; Cellular Reprogramming; Dinoprostone; Energy Metabolism; Gene Expression Regulation; Glycolysis; Humans; Immunoglobulin G; Interleukin-1beta; Kidney; Lupus Nephritis; Macrophages; Mice; Mice, Inbred C57BL; Mice, Knockout; Reactive Oxygen Species; Receptors, IgG
PubMed: 32541026
DOI: 10.1073/pnas.2000943117 -
Immunity Jun 2023Type 1 conventional dendritic cells (cDC1s) are critical for anti-cancer immunity. Protective anti-cancer immunity is thought to require cDC1s to sustain T cell...
Type 1 conventional dendritic cells (cDC1s) are critical for anti-cancer immunity. Protective anti-cancer immunity is thought to require cDC1s to sustain T cell responses within tumors, but it is poorly understood how this function is regulated and whether its subversion contributes to immune evasion. Here, we show that tumor-derived prostaglandin E2 (PGE) programmed a dysfunctional state in intratumoral cDC1s, disabling their ability to locally orchestrate anti-cancer CD8 T cell responses. Mechanistically, cAMP signaling downstream of the PGE-receptors EP2 and EP4 was responsible for the programming of cDC1 dysfunction, which depended on the loss of the transcription factor IRF8. Blockade of the PGE-EP2/EP4-cDC1 axis prevented cDC1 dysfunction in tumors, locally reinvigorated anti-cancer CD8 T cell responses, and achieved cancer immune control. In human cDC1s, PGE-induced dysfunction is conserved and associated with poor cancer patient prognosis. Our findings reveal a cDC1-dependent intratumoral checkpoint for anti-cancer immunity that is targeted by PGE for immune evasion.
Topics: Humans; Dinoprostone; Neoplasms; Antibodies; CD8-Positive T-Lymphocytes; Dendritic Cells; Receptors, Prostaglandin E
PubMed: 37315536
DOI: 10.1016/j.immuni.2023.05.011 -
The Journal of Clinical Investigation May 2022Obesity-associated complications are causing increasing morbidity and mortality worldwide. Expansion of adipose tissue in obesity leads to a state of low-grade chronic...
Obesity-associated complications are causing increasing morbidity and mortality worldwide. Expansion of adipose tissue in obesity leads to a state of low-grade chronic inflammation and dysregulated metabolism, resulting in insulin resistance and metabolic syndrome. Adipose tissue macrophages (ATMs) accumulate in obesity and are a source of proinflammatory cytokines that further aggravate adipocyte dysfunction. Macrophages are rich sources of cyclooxygenase (COX), the rate limiting enzyme for prostaglandin E2 (PGE2) production. When mice were fed a high-fat diet (HFD), ATMs increased expression of COX-2. Selective myeloid cell COX-2 deletion resulted in increased monocyte recruitment and proliferation of ATMs, leading to increased proinflammatory ATMs with decreased phagocytic ability. There were increased weight gain and adiposity, decreased peripheral insulin sensitivity and glucose utilization, increased adipose tissue inflammation and fibrosis, and abnormal adipose tissue angiogenesis. HFD pair-feeding led to similar increases in body weight, but mice with selective myeloid cell COX-2 still exhibited decreased peripheral insulin sensitivity and glucose utilization. Selective myeloid deletion of the macrophage PGE2 receptor subtype, EP4, produced a similar phenotype, and a selective EP4 agonist ameliorated the metabolic abnormalities seen with ATM COX-2 deletion. Therefore, these studies demonstrated that an ATM COX-2/PGE2/EP4 axis plays an important role in inhibiting adipose tissue dysfunction.
Topics: Adipose Tissue; Animals; Cyclooxygenase 2; Dinoprostone; Glucose; Inflammation; Insulin Resistance; Macrophages; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity
PubMed: 35499079
DOI: 10.1172/JCI152391 -
Theranostics 2023Immune checkpoint blockers (ICBs) are revolutionized therapeutic strategies for cancer, but most patients with solid neoplasms remain resistant to ICBs, partly because...
Immune checkpoint blockers (ICBs) are revolutionized therapeutic strategies for cancer, but most patients with solid neoplasms remain resistant to ICBs, partly because of the difficulty in reversing the highly immunosuppressive tumor microenvironment (TME). Exploring the strategies for tumor immunotherapy is highly dependent on the discovery of molecular mechanisms of tumor immune escape and potential therapeutic target. Krüppel-like Factor 5 (KLF5) is a cell-intrinsic oncogene to promote tumorigenesis. However, the cell-extrinsic effects of KLF5 on suppressing the immune response to cancer remain unclear. We analyzed the immunosuppressive role of KLF5 in mice models transplanted with KLF5-deleted/overexpressing tumor cells. We performed RNA sequencing, immunohistochemistry, western blotting, real time-PCR, ELISA, luciferase assay, chromatin immunoprecipitation (ChIP), and flow cytometry to demonstrate the effects of KLF5 on CD8 T cell infiltration and related molecular mechanism. Single-cell RNA sequencing and spatial transcriptomics analysis were applied to further decipher the association between KLF5 expression and infiltrating immune cells. The efficacy of KLF5/COX2 inhibitors combined with anti-programmed cell death protein 1 (anti-PD1) therapy were explored in pre-clinical models. Finally, a gene-expression signature depending on KLF5/COX2 axis and associated immune markers was created to predict patient survival. KLF5 inactivation decelerated basal-like breast tumor growth in a CD8 T-cell-dependent manner. Transcriptomic profiling revealed that KLF5 loss in tumors increases the number and activated function of T lymphocytes. Mechanistically, KLF5 binds to the promoter of the COX2 gene and promotes COX2 transcription; subsequently, KLF5 deficiency decreases prostaglandin E2 (PGE2) release from tumor cells by reducing COX2 expression. Inhibition of the KLF5/COX2 axis increases the number and functionality of intratumoral antitumor T cells to synergize the antitumorigenic effects of anti-PD1 therapy. Analysis of patient datasets at single-cell and spatial resolution shows that low expression of KLF5 is associated with an immune-supportive TME. Finally, we generate a KLF5/COX2-associated immune score (KC-IS) to predict patient survival. Our results identified a novel mechanism responsible for KLF5-mediated immunosuppression in TME, and targeting the KLF5/COX2/PGE2 axis is a critical immunotherapy sensitizer.
Topics: Mice; Animals; Cyclooxygenase 2; Dinoprostone; Transcription Factors; Immunotherapy; CD8-Positive T-Lymphocytes; Tumor Microenvironment; Cell Line, Tumor; Kruppel-Like Transcription Factors
PubMed: 36923542
DOI: 10.7150/thno.82182 -
Blood Aug 2022
Topics: Dinoprostone; Immunosuppressive Agents; Lung; Neutrophils
PubMed: 36006676
DOI: 10.1182/blood.2022017345 -
Molecular Neurobiology Mar 2022Cerebral ischemia reperfusion (I/R) injury easily develops in ischemic stroke, resulting in more serious injury. Ferroptosis is involved in cerebral I/R injury, but the...
Cerebral ischemia reperfusion (I/R) injury easily develops in ischemic stroke, resulting in more serious injury. Ferroptosis is involved in cerebral I/R injury, but the mechanism remains unclear. Prostaglandin E2 (PGE2) is potential to regulate ferroptosis. This study mainly explored the regulation effects of PGE2 on ferroptosis induced by cerebral I/R. We first detected PGE2 levels and ferroptosis status in 11 human brain tissues. Then, we induced a cerebral I/R animal model to examine ferroptosis status in cerebral I/R. We further injected a ferroptosis inhibitor to define the response of the PGE2 pathway to ferroptosis. Finally, we injected PGE2 and pranoprofen to explore the regulation of the cyclooxygenases 2 (COX-2)/PGE2 pathway on ferroptosis in cerebral I/R. We found that PGE2 release was correlated with the levels of reactive oxygen species, malondialdehyde, glutathione peroxidase 4, COX-2, and Spermidine/spermine N1-acetyltransferase 1. Ferroptosis can be induced by cerebral I/R, while inhibition of ferroptosis induced by cerebral I/R can inactivate PGE2 synthases, degrade enzyme, and parts of PGE2 receptors, and reduce cerebral infarct volume. In turn, PGE2 inhibited ferroptosis through the reduction of Fe, glutathione oxidation, and lipid peroxidation, while pranoprofen, one of the COX inhibitors, played an opposite role. In conclusion, PGE2 was positively correlated with ferroptosis, inhibition of ferroptosis induced by cerebral I/R can inactivate COX-2/PGE2 pathway, and PGE2 inhibited ferroptosis induced by cerebral I/R, possibly via PGE2 receptor 3 and PGE2 receptor 4. Graphical abstract Inhibition of ferroptosis inactivates the COX-2/PGE2 pathway. Cerebral ischemia reperfusion injury induces the secretion of PGE2. After the inhibition of ferroptosis by Fer-1, the expression of cyclooxygenases (COX-1 and COX-2) decreased, and PGE2 synthases cPGES, mPGES-1, and mPGES-2 were also reduced. At the same time, the PGE2 degradation enzyme 15-PGDH was also reduced. Changes in these enzymes ultimately result in the declination of PGE2. Besides, the expression of PGE2 receptors EP3 and EP4 is also inhibited, indicating that the function they mediate is also impaired. In conclusion, after cerebral ischemia reperfusion injury, the inhibition of ferroptosis inactivates the COX-2/PGE2 pathway.
Topics: Animals; Cerebral Infarction; Cyclooxygenase 2; Dinoprostone; Ferroptosis; Humans; Reperfusion; Reperfusion Injury
PubMed: 35013936
DOI: 10.1007/s12035-021-02706-1 -
Journal of Biomedical Science Aug 2023Excess polymorphonuclear neutrophil (PMN) recruitment or excessive neutrophil extracellular trap (NET) formation can lead to the development of multiple organ...
BACKGROUND
Excess polymorphonuclear neutrophil (PMN) recruitment or excessive neutrophil extracellular trap (NET) formation can lead to the development of multiple organ dysfunction during sepsis. M2 macrophage-derived exosomes (M2-Exos) have exhibited anti-inflammatory activities in some inflammatory diseases to mediate organ functional protection, but their role in treating sepsis-related acute lung injury (ALI) remains unclear. In this study, we sought to investigate whether M2-Exos could prevent potentially deleterious inflammatory effects during sepsis-related ALI by modulating abnormal PMN behaviours.
METHODS
C57BL/6 wild-type mice were subjected to a caecal ligation and puncture (CLP) mouse model to mimic sepsis in vivo, and M2-Exos were administered intraperitoneally 1 h after CLP. H&E staining, immunofluorescence and immunohistochemistry were conducted to investigate lung tissue injury, PMN infiltration and NET formation in the lung. We further demonstrated the role of M2-Exos on PMN function and explored the potential mechanisms through an in vitro coculture experiment using PMNs isolated from both healthy volunteers and septic patients.
RESULTS
Here, we report that M2-Exos inhibited PMN migration and NET formation, alleviated lung injury and reduced mortality in a sepsis mouse model. In vitro, M2-Exos significantly decreased PMN migration and NET formation capacity, leading to lipid mediator class switching from proinflammatory leukotriene B4 (LTB4) to anti-inflammatory lipoxin A4 (LXA4) by upregulating 15-lipoxygenase (15-LO) expression in PMNs. Treatment with LXA4 receptor antagonist attenuated the effect of M2-Exos on PMNs and lung injury. Mechanistically, prostaglandin E2 (PGE2) enriched in M2-Exos was necessary to increase 15-LO expression in PMNs by functioning on the EP4 receptor, upregulate LXA4 production to downregulate chemokine (C-X-C motif) receptor 2 (CXCR2) and reactive oxygen species (ROS) expressions, and finally inhibit PMN function.
CONCLUSIONS
Our findings reveal a previously unknown role of M2-Exos in regulating PMN migration and NET formation through lipid mediator class switching, thus highlighting the potential application of M2-Exos in controlling PMN-mediated tissue injury in patients with sepsis.
Topics: Mice; Animals; Dinoprostone; Neutrophils; Neutrophil Infiltration; Extracellular Traps; Lung Injury; Immunoglobulin Class Switching; Mice, Inbred C57BL; Sepsis; Macrophages; Platelet Activating Factor
PubMed: 37533081
DOI: 10.1186/s12929-023-00957-9 -
Clinical Hemorheology and... 2022Lipoxins and ATL appear to be the first recognized members of a new class of endogenous mediator that are anti-inflammatory or serve for the "pro-resolution" of...
Lipoxins and ATL appear to be the first recognized members of a new class of endogenous mediator that are anti-inflammatory or serve for the "pro-resolution" of inflammation. PGE2 can and may display anti-inflammatory properties in certain settings, but in most cases, it enhances inflammation in vivo. This is likely the result of numerous receptor isoforms and differential coupled mechanisms for PGE2 and its diverse role in human physiology. Since the integrated response of the host is essential to health and disease, it is important to achieve a more complete understanding of the molecular and cellular events governing the formation and actions of endogenous mediators of resolution that appear to control the magnitude and duration of inflammation. In view of the present body of evidence, it is not surprising that a protective action for inhibition of COX-2 was found in cardiovascular disease. Characterizing useful experimental systems with clinically relevant endpoints will also take a multidisciplinary approach and require a shift in our current thinking about inflammation and the role of lipid mediators.
Topics: Humans; Lipoxins; Aspirin; Dinoprostone; Inflammation Mediators; Inflammation; Anti-Inflammatory Agents
PubMed: 35147530
DOI: 10.3233/CH-211346