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mPGES-1-Mediated Production of PGE and EP4 Receptor Sensing Regulate T Cell Colonic Inflammation.
Maseda D, Banerjee A, Johnson EM, Washington MK, Kim H, Lau KS, Crofford LJ
(2018) Front Immunol 9: 2954
MeSH Terms: Animals, CD4-Positive T-Lymphocytes, Colitis, Dinoprostone, Intestinal Mucosa, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Nuclear Receptor Subfamily 1, Group F, Member 3, Prostaglandin-E Synthases, Receptors, Prostaglandin E, EP2 Subtype, Receptors, Prostaglandin E, EP4 Subtype, T-Lymphocytes, T-Lymphocytes, Regulatory
Show Abstract · Added March 25, 2020
PGE is a lipid mediator of the initiation and resolution phases of inflammation, as well as a regulator of immune system responses to inflammatory events. PGE is produced and sensed by T cells, and autocrine or paracrine PGE can affect T cell phenotype and function. In this study, we use a T cell-dependent model of colitis to evaluate the role of PGE on pathological outcome and T-cell phenotypes. CD4 T effector cells either deficient in mPGES-1 or the PGE receptor EP4 are less colitogenic. Absence of T cell autocrine mPGES1-dependent PGE reduces colitogenicity in association with an increase in CD4RORγt cells in the lamina propria. In contrast, recipient mice deficient in mPGES-1 exhibit more severe colitis that corresponds with a reduced capacity to generate FoxP3 T cells, especially in mesenteric lymph nodes. Thus, our research defines how mPGES-1-driven production of PGE by different cell types in distinct intestinal locations impacts T cell function during colitis. We conclude that PGE has profound effects on T cell phenotype that are dependent on the microenvironment.
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Intestinal host defense outcome is dictated by PGE production during efferocytosis of infected cells.
Dejani NN, Orlando AB, Niño VE, Penteado LA, Verdan FF, Bazzano JMR, Codo AC, Salina ACG, Saraiva AC, Avelar MR, Spolidorio LC, Serezani CH, Medeiros AI
(2018) Proc Natl Acad Sci U S A 115: E8469-E8478
MeSH Terms: Animals, Citrobacter rodentium, Colitis, Dendritic Cells, Dinoprostone, Enterobacteriaceae Infections, Female, Intestines, Macrophages, Mice, Receptors, Prostaglandin E, EP4 Subtype
Show Abstract · Added March 18, 2020
Inflammatory responses are terminated by the clearance of dead cells, a process termed efferocytosis. A consequence of efferocytosis is the synthesis of the antiinflammatory mediators TGF-β, PGE, and IL-10; however, the efferocytosis of infected cells favors Th17 responses by eliciting the synthesis of TGF-β, IL-6, and IL-23. Recently, we showed that the efferocytosis of apoptotic -infected macrophages by dendritic cells triggers PGE production in addition to pro-Th17 cytokine expression. We therefore examined the role of PGE during Th17 differentiation and intestinal pathology. The efferocytosis of apoptotic -infected cells by dendritic cells promoted high levels of PGE, which impaired IL-1R expression via the EP4-PKA pathway in T cells and consequently inhibited Th17 differentiation. The outcome of murine intestinal infection was dependent on the EP4 receptor. Infected mice treated with EP4 antagonist showed enhanced intestinal defense against compared with infected mice treated with vehicle control. Those results suggest that EP4 signaling during infectious colitis could be targeted as a way to enhance Th17 immunity and host defense.
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Protective Role of mPGES-1 (Microsomal Prostaglandin E Synthase-1)-Derived PGE (Prostaglandin E) and the Endothelial EP4 (Prostaglandin E Receptor) in Vascular Responses to Injury.
Hao H, Hu S, Wan Q, Xu C, Chen H, Zhu L, Xu Z, Meng J, Breyer RM, Li N, Liu DP, FitzGerald GA, Wang M
(2018) Arterioscler Thromb Vasc Biol 38: 1115-1124
MeSH Terms: Animals, Cell Adhesion, Cell Proliferation, Cells, Cultured, Dinoprostone, Disease Models, Animal, Endothelial Cells, Female, Femoral Artery, Humans, Leukocytes, Male, Mice, Inbred C57BL, Mice, Knockout, Muscle, Smooth, Neointima, Prostaglandin-E Synthases, Re-Epithelialization, Receptors, Epoprostenol, Receptors, Prostaglandin E, EP4 Subtype, Signal Transduction, Vascular System Injuries
Show Abstract · Added May 29, 2018
OBJECTIVE - Deletion of mPGES-1 (microsomal prostaglandin E synthase-1)-an anti-inflammatory target alternative to COX (cyclooxygenase)-2-attenuates injury-induced neointima formation in mice. This is attributable to the augmented levels of PGI (prostacyclin)-a known restraint of the vascular response to injury, acting via IP (I prostanoid receptor). To examine the role of mPGES-1-derived PGE (prostaglandin E) in vascular remodeling without the IP.
APPROACH AND RESULTS - Mice deficient in both IP and mPGES-1 (DKO [double knockout] and littermate controls [IP KO (knockout)]) were subjected to angioplasty wire injury. Compared with the deletion of IP alone, coincident deletion of IP and mPGES-1 increased neointima formation, without affecting media area. Early pathological changes include impaired reendothelialization and increased leukocyte invasion in neointima. Endothelial cells (ECs), but not vascular smooth muscle cells, isolated from DKOs exhibited impaired cell proliferation. Activation of EP (E prostanoid receptor) 4 (and EP2, to a lesser extent), but not of EP1 or EP3, promoted EC proliferation. EP4 antagonism inhibited proliferation of mPGES-1-competent ECs, but not of mPGES-1-deficient ECs, which showed suppressed PGE production. EP4 activation inhibited leukocyte adhesion to ECs in vitro, promoted reendothelialization, and limited neointima formation post-injury in the mouse. Endothelium-restricted deletion of EP4 in mice suppressed reendothelialization, increased neointimal leukocytes, and exacerbated neointimal formation.
CONCLUSIONS - Removal of the IP receptors unmasks a protective role of mPGES-1-derived PGE in limiting injury-induced vascular hyperplasia. EP4, in the endothelial compartment, is essential to promote reendothelialization and restrain neointimal formation after injury. Activating EP4 bears therapeutic potential to prevent restenosis after percutaneous coronary intervention.
© 2018 American Heart Association, Inc.
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mPGES1-Dependent Prostaglandin E (PGE) Controls Antigen-Specific Th17 and Th1 Responses by Regulating T Autocrine and Paracrine PGE Production.
Maseda D, Johnson EM, Nyhoff LE, Baron B, Kojima F, Wilhelm AJ, Ward MR, Woodward JG, Brand DD, Crofford LJ
(2018) J Immunol 200: 725-736
MeSH Terms: Animals, Autocrine Communication, Dinoprostone, Epitopes, T-Lymphocyte, Gene Expression Regulation, Immunization, Immunomodulation, Lymphocyte Activation, Mice, Paracrine Communication, Phenotype, Prostaglandin-E Synthases, Receptors, Prostaglandin E, EP2 Subtype, Receptors, Prostaglandin E, EP4 Subtype, Th1 Cells, Th17 Cells
Show Abstract · Added March 25, 2020
The integration of inflammatory signals is paramount in controlling the intensity and duration of immune responses. Eicosanoids, particularly PGE, are critical molecules in the initiation and resolution of inflammation and in the transition from innate to acquired immune responses. Microsomal PGE synthase 1 (mPGES1) is an integral membrane enzyme whose regulated expression controls PGE levels and is highly expressed at sites of inflammation. PGE is also associated with modulation of autoimmunity through altering the IL-23/IL-17 axis and regulatory T cell (Treg) development. During a type II collagen-CFA immunization response, lack of mPGES1 impaired the numbers of CD4 regulatory (Treg) and Th17 cells in the draining lymph nodes. Ag-experienced mPGES1 CD4 cells showed impaired IL-17A, IFN-γ, and IL-6 production when rechallenged ex vivo with their cognate Ag compared with their wild-type counterparts. Additionally, production of PGE by cocultured APCs synergized with that of Ag-experienced CD4 T cells, with mPGES1 competence in the APC compartment enhancing CD4 IL-17A and IFN-γ responses. However, in contrast with CD4 cells that were Ag primed in vivo, exogenous PGE inhibited proliferation and skewed IL-17A to IFN-γ production under Th17 polarization of naive T cells in vitro. We conclude that mPGES1 is necessary in vivo to mount optimal Treg and Th17 responses during an Ag-driven primary immune response. Furthermore, we uncover a coordination of autocrine and paracrine mPGES1-driven PGE production that impacts effector T cell IL-17A and IFN-γ responses.
Copyright © 2018 by The American Association of Immunologists, Inc.
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Efferocytosis-induced prostaglandin E2 production impairs alveolar macrophage effector functions during Streptococcus pneumoniae infection.
Salina AC, Souza TP, Serezani CH, Medeiros AI
(2017) Innate Immun 23: 219-227
MeSH Terms: Animals, Apoptosis, Bacteriolysis, Cyclic AMP, Cyclic AMP-Dependent Protein Kinases, Dinoprostone, Female, Homeostasis, Humans, Hydrogen Peroxide, Jurkat Cells, Macrophages, Alveolar, Phagocytosis, Pneumococcal Infections, Rats, Rats, Wistar, Receptors, Prostaglandin E, EP2 Subtype, Receptors, Prostaglandin E, EP4 Subtype, Signal Transduction, Streptococcus pneumoniae
Show Abstract · Added May 4, 2017
Alveolar macrophages (AMs) are multitasking cells that maintain lung homeostasis by clearing apoptotic cells (efferocytosis) and performing antimicrobial effector functions. Different PRRs have been described to be involved in the binding and capture of non-opsonized Streptococcus pneumoniae, such as TLR-2, mannose receptor (MR) and scavenger receptors (SRs). However, the mechanism by which the ingestion of apoptotic cells negatively influences the clearance of non-opsonized S. pneumoniae remains to be determined. In this study, we evaluated whether the prostaglandin E2 (PGE) produced during efferocytosis by AMs inhibits the ingestion and killing of non-opsonized S. pneumoniae. Resident AMs were pre-treated with an E prostanoid (EP) receptor antagonist, inhibitors of cyclooxygenase and protein kinase A (PKA), incubated with apoptotic Jurkat T cells, and then challenged with S. pneumoniae. Efferocytosis slightly decreased the phagocytosis of S. pneumoniae but greatly inhibited bacterial killing by AMs in a manner dependent on PGE production, activation of the EP2-EP4/cAMP/PKA pathway and inhibition of HO production. Our data suggest that the PGE produced by AMs during efferocytosis inhibits HO production and impairs the efficient clearance non-opsonized S. pneumoniae by EP2-EP4/cAMP/PKA pathway.
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20 MeSH Terms
Macrophage Cyclooxygenase-2 Protects Against Development of Diabetic Nephropathy.
Wang X, Yao B, Wang Y, Fan X, Wang S, Niu A, Yang H, Fogo A, Zhang MZ, Harris RC
(2017) Diabetes 66: 494-504
MeSH Terms: Albuminuria, Animals, Cells, Cultured, Cyclooxygenase 2, Diabetes Mellitus, Experimental, Diabetes Mellitus, Type 1, Diabetic Nephropathies, Fibrosis, Immunoblotting, Immunohistochemistry, Kidney, Macrophages, Male, Mice, Mice, Knockout, NF-kappa B, Neutrophil Infiltration, Neutrophils, Nitric Oxide Synthase Type II, Real-Time Polymerase Chain Reaction, Receptors, Prostaglandin E, Receptors, Prostaglandin E, EP4 Subtype, Signal Transduction, T-Lymphocytes
Show Abstract · Added April 26, 2017
Diabetic nephropathy (DN) is characterized by increased macrophage infiltration, and proinflammatory M1 macrophages contribute to development of DN. Previous studies by us and others have reported that macrophage cyclooxygenase-2 (COX-2) plays a role in polarization and maintenance of a macrophage tissue-reparative M2 phenotype. We examined the effects of macrophage COX-2 on development of DN in type 1 diabetes. Cultured macrophages with COX-2 deletion exhibited an M1 phenotype, as demonstrated by higher inducible nitric oxide synthase and nuclear factor-κB levels but lower interleukin-4 receptor-α levels. Compared with corresponding wild-type diabetic mice, mice with COX-2 deletion in hematopoietic cells (COX-2 knockout bone marrow transplantation) or macrophages (CD11b-Cre COX2) developed severe DN, as indicated by increased albuminuria, fibrosis, and renal infiltration of T cells, neutrophils, and macrophages. Although diabetic kidneys with macrophage COX-2 deletion had more macrophage infiltration, they had fewer renal M2 macrophages. Diabetic kidneys with macrophage COX-2 deletion also had increased endoplasmic reticulum stress and decreased number of podocytes. Similar results were found in diabetic mice with macrophage PGE receptor subtype 4 deletion. In summary, these studies have demonstrated an important but unexpected role for macrophage COX-2/prostaglandin E/PGE receptor subtype 4 signaling to lessen progression of diabetic kidney disease, unlike the pathogenic effects of increased COX-2 expression in intrinsic renal cells.
© 2017 by the American Diabetes Association.
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24 MeSH Terms
Opposing roles of LTB4 and PGE2 in regulating the inflammasome-dependent scorpion venom-induced mortality.
Zoccal KF, Sorgi CA, Hori JI, Paula-Silva FW, Arantes EC, Serezani CH, Zamboni DS, Faccioli LH
(2016) Nat Commun 7: 10760
MeSH Terms: Animals, Arachidonate 5-Lipoxygenase, Blotting, Western, Carrier Proteins, Celecoxib, Cyclic AMP, Cyclic AMP-Dependent Protein Kinases, Cyclooxygenase Inhibitors, Dinoprostone, In Vitro Techniques, Indoles, Indomethacin, Inflammasomes, Interleukin-1beta, Leukotriene B4, Lipoxygenase Inhibitors, Macrophages, Macrophages, Peritoneal, Mice, Mice, Knockout, NF-kappa B, NLR Family, Pyrin Domain-Containing 3 Protein, Phosphoproteins, Prostaglandin Antagonists, Receptors, Prostaglandin E, EP2 Subtype, Receptors, Prostaglandin E, EP4 Subtype, Reverse Transcriptase Polymerase Chain Reaction, Scorpion Stings, Scorpion Venoms, Scorpions, Xanthones
Show Abstract · Added May 4, 2017
Tityus serrulatus sting causes thousands of deaths annually worldwide. T. serrulatus-envenomed victims exhibit local or systemic reaction that culminates in pulmonary oedema, potentially leading to death. However, the molecular mechanisms underlying T. serrulatus venom (TsV) activity remain unknown. Here we show that TsV triggers NLRP3 inflammasome activation via K(+) efflux. Mechanistically, TsV triggers lung-resident cells to release PGE2, which induces IL-1β production via E prostanoid receptor 2/4-cAMP-PKA-NFκB-dependent mechanisms. IL-1β/IL-1R actions account for oedema and neutrophil recruitment to the lungs, leading to TsV-induced mortality. Inflammasome activation triggers LTB4 production and further PGE2 via IL-1β/IL-1R signalling. Activation of LTB4-BLT1/2 pathway decreases cAMP generation, controlling TsV-induced inflammation. Exogenous administration confirms LTB4 anti-inflammatory activity and abrogates TsV-induced mortality. These results suggest that the balance between LTB4 and PGE2 determines the amount of IL-1β inflammasome-dependent release and the outcome of envenomation. We suggest COX1/2 inhibition as an effective therapeutic intervention for scorpion envenomation.
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31 MeSH Terms
Prostaglandin E receptor 4 (EP4) promotes colonic tumorigenesis.
Chang J, Vacher J, Yao B, Fan X, Zhang B, Harris RC, Zhang MZ
(2015) Oncotarget 6: 33500-11
MeSH Terms: Animals, Carcinogenesis, Colorectal Neoplasms, Cyclooxygenase 2, Disease Models, Animal, Female, MAP Kinase Signaling System, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Myeloid Cells, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins c-akt, RAW 264.7 Cells, Receptors, Prostaglandin E, EP4 Subtype, TOR Serine-Threonine Kinases
Show Abstract · Added May 5, 2017
Colorectal cancer (CRC) continues to be a major cause of morbidity and mortality. Although the factors underlying CRC development and progression are multifactorial, there is an important role for tumor-host interactions, especially interactions with myeloid cells. There is also increasing evidence that cyclooxygenase-derived prostaglandins are important mediators of CRC development and growth. Although prevention trials with either nonselective NSAIDs or COX-2 selective agents have shown promise, the gastrointestinal or cardiovascular side effects of these agents have limited their implementation. The predominant prostaglandin involved in CRC pathogenesis is PGE2. Since myeloid cells express high levels of the PGE2 receptor subtype, EP4, we selectively ablated EP4 in myeloid cells and studied adenoma formation in a mouse model of intestinal adenomatous polyposis, ApcMin/+ mice. ApcMin/+mice with selective myeloid cell deletion of EP4 had marked inhibition of both adenoma number and size, with associated decreases in mTOR and ERK activation. Either genetic or pharmacologic inhibition of EP4 receptors led to an anti-tumorigenic M1 phenotype of macrophages/dendritic cells. Therefore, PGE2-mediated EP4 signaling in myeloid cells promotes tumorigenesis, suggesting EP4 as a potentially attractive target for CRC chemoprevention or treatment.
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17 MeSH Terms
Prostaglandin signalling regulates ciliogenesis by modulating intraflagellar transport.
Jin D, Ni TT, Sun J, Wan H, Amack JD, Yu G, Fleming J, Chiang C, Li W, Papierniak A, Cheepala S, Conseil G, Cole SP, Zhou B, Drummond IA, Schuetz JD, Malicki J, Zhong TP
(2014) Nat Cell Biol 16: 841-51
MeSH Terms: Amino Acid Sequence, Animals, Base Sequence, Cilia, Dinoprostone, HEK293 Cells, Humans, Kupffer Cells, Mice, Molecular Sequence Data, Multidrug Resistance-Associated Proteins, Protein Transport, Receptors, Prostaglandin E, EP4 Subtype, Signal Transduction, Transport Vesicles, Zebrafish, Zebrafish Proteins
Show Abstract · Added February 19, 2015
Cilia are microtubule-based organelles that mediate signal transduction in a variety of tissues. Despite their importance, the signalling cascades that regulate cilium formation remain incompletely understood. Here we report that prostaglandin signalling affects ciliogenesis by regulating anterograde intraflagellar transport (IFT). Zebrafish leakytail (lkt) mutants show ciliogenesis defects, and the lkt locus encodes an ATP-binding cassette transporter (ABCC4). We show that Lkt/ABCC4 localizes to the cell membrane and exports prostaglandin E2 (PGE2), a function that is abrogated by the Lkt/ABCC4(T804M) mutant. PGE2 synthesis enzyme cyclooxygenase-1 and its receptor, EP4, which localizes to the cilium and activates the cyclic-AMP-mediated signalling cascade, are required for cilium formation and elongation. Importantly, PGE2 signalling increases anterograde but not retrograde velocity of IFT and promotes ciliogenesis in mammalian cells. These findings lead us to propose that Lkt/ABCC4-mediated PGE2 signalling acts through a ciliary G-protein-coupled receptor, EP4, to upregulate cAMP synthesis and increase anterograde IFT, thereby promoting ciliogenesis.
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17 MeSH Terms
Suppression of Alzheimer-associated inflammation by microglial prostaglandin-E2 EP4 receptor signaling.
Woodling NS, Wang Q, Priyam PG, Larkin P, Shi J, Johansson JU, Zagol-Ikapitte I, Boutaud O, Andreasson KI
(2014) J Neurosci 34: 5882-94
MeSH Terms: Aged, Aged, 80 and over, Alzheimer Disease, Amyloid beta-Peptides, Animals, Cell Survival, Humans, Inflammation, Methyl Ethers, Microglia, Peptide Fragments, Receptors, Prostaglandin E, EP4 Subtype, Signal Transduction
Show Abstract · Added January 22, 2015
A persistent and nonresolving inflammatory response to accumulating Aβ peptide species is a cardinal feature in the development of Alzheimer's disease (AD). In response to accumulating Aβ peptide species, microglia, the innate immune cells of the brain, generate a toxic inflammatory response that accelerates synaptic and neuronal injury. Many proinflammatory signaling pathways are linked to progression of neurodegeneration. However, endogenous anti-inflammatory pathways capable of suppressing Aβ-induced inflammation represent a relatively unexplored area. Here we report that signaling through the prostaglandin-E2 (PGE2) EP4 receptor potently suppresses microglial inflammatory responses to Aβ42 peptides. In cultured microglial cells, EP4 stimulation attenuated levels of Aβ42-induced inflammatory factors and potentiated phagocytosis of Aβ42. Microarray analysis demonstrated that EP4 stimulation broadly opposed Aβ42-driven gene expression changes in microglia, with enrichment for targets of IRF1, IRF7, and NF-κB transcription factors. In vivo, conditional deletion of microglial EP4 in APPSwe-PS1ΔE9 (APP-PS1) mice conversely increased inflammatory gene expression, oxidative protein modification, and Aβ deposition in brain at early stages of pathology, but not at later stages, suggesting an early anti-inflammatory function of microglial EP4 signaling in the APP-PS1 model. Finally, EP4 receptor levels decreased significantly in human cortex with progression from normal to AD states, suggesting that early loss of this beneficial signaling system in preclinical AD development may contribute to subsequent progression of pathology.
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13 MeSH Terms