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Frontiers in Immunology 2023The specific effect of Adipose-Derived Mesenchymal Stem Cells (Ad-MSC) on acute joint inflammation, where the response mostly depends on innate immunity activation,...
OBJECTIVE
The specific effect of Adipose-Derived Mesenchymal Stem Cells (Ad-MSC) on acute joint inflammation, where the response mostly depends on innate immunity activation, remains elusive. The pathogenesis of gouty arthritis, characterized by the deposition of monosodium urate (MSU) crystals in the joints, associated to acute flares, has been associated to NLRP3 inflammasome activation and subsequent amplification of the inflammatory response. Our aim was to study the effect of human Ad-MSC administration in the clinical inflammatory response of rabbits after MSU injection, and the molecular mechanisms involved.
METHODS
Ad-MSC were administered by intraarterial route shortly after intraarticular MSU crystal injections. Joint and systemic inflammation was sequentially studied, and the mechanisms involved in NLRP3 inflammasome activation, and the synthesis of inflammatory mediators were assessed in the synovial membranes 72h after insult. Ad-MSC and THP-1-derived macrophages stimulated with MSU were co-cultured in transwell system.
RESULTS
A single systemic dose of Ad-MSC accelerated the resolution of local and systemic inflammatory response. In the synovial membrane, Ad-MSC promoted alternatively M2 macrophage presence, inhibiting NLRP3 inflammasome and inducing the production of anti-inflammatory cytokines, such as IL-10 or TGF-β, and decreasing nuclear factor-κB activity. Ad-MSC induced a net anti-inflammatory balance in MSU-stimulated THP-1 cells, with a higher increase in IL-10 and IDO expression than that observed for IL-1β and TNF.
CONCLUSION
Our and results showed that a single systemic dose of Ad-MSC decrease the intensity and duration of the inflammatory response by an early local COX-2 upregulation and PGE release. Ad-MSCs suppressed NF-kB activity, NLRP3 inflammasome, and promoted the presence of M2 alternative macrophages in the synovium. Therefore, this therapeutic approach could be considered as a pharmacological alternative in patients with comorbidities that preclude conventional treatment.
Topics: Animals; Humans; Rabbits; Anti-Inflammatory Agents; Arthritis, Gouty; Cyclooxygenase 2; Inflammasomes; Inflammation; Interleukin-10; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; Uric Acid; Mesenchymal Stem Cell Transplantation
PubMed: 37533852
DOI: 10.3389/fimmu.2023.1193179 -
Signal Transduction and Targeted Therapy Sep 2023
Topics: Receptors, Prostaglandin; Glucose; Cardiomegaly
PubMed: 37669930
DOI: 10.1038/s41392-023-01541-1 -
The Journal of Allergy and Clinical... Aug 2023Chronic rhinosinusitis (CRS) can be divided into endotypes by functional or pathophysiologic findings.
BACKGROUND
Chronic rhinosinusitis (CRS) can be divided into endotypes by functional or pathophysiologic findings.
OBJECTIVE
The aim of this study was to analyze the expression of cytokines, prostaglandin (PG) synthases, and their receptors related to the pathogenesis of CRS, especially those contributing to nasal polyp (NP) formation.
METHODS
NPs and uncinate tissue (UT) samples were collected from 90 patients who underwent endoscopic sinus surgery. They included 75 patients with CRS (including 45 with eosinophilic CRS [eCRS] and 30 with non-eCRS) and 15 patients without CRS. A total of 30 genes were selected for our original DNA array plate to analyze the levels of expression of 10 cytokines (IFN-γ, IL-4, IL-5, IL-10, IL-13, IL-17A, IL-22, IL-25, IL-33, and TSLP), 4 prostaglandin synthases (prostaglandin D [PGD] synthase, prostaglandin E synthase, COX-1, and COX-2), and their 16 receptors. Clustering analysis was performed according to the expression results, and clinical findings of patients from each cluster were investigated.
RESULTS
The samples could be divided into 3 clusters. Cluster 1 showed elevated levels of expression of (ST2 [an IL-33 receptor]), , and (CRTH2, a PGD receptor); cluster 2 showed elevated levels of expression of and ; and cluster 3 showed an elevated level of expression of . Regarding clinical features, the main characteristics of each cluster were as follows: NPs from patients with eCRS for cluster 1, NPs and/or UT samples from patients with non-eCRS for cluster 2, and UTs from patients with non-CRS for cluster 3.
CONCLUSION
The results suggest that there are associations between type 2 inflammation/PGD and eCRS and also between type 3 inflammation/prostaglandin E and non-eCRS.
PubMed: 37779524
DOI: 10.1016/j.jacig.2023.100123 -
Veterinary Research Communications Sep 2023Bovine in vitro endometrial models that resemble tissue function in vivo are needed to study infertility, long-term uterine alterations induced by pathogens and impact...
Bovine in vitro endometrial models that resemble tissue function in vivo are needed to study infertility, long-term uterine alterations induced by pathogens and impact of endocrine disruptor chemicals on reproductive function and other reproductive system complications that cause high economic losses in livestock species. The present study aimed to generate an innovative, reproducible, and functional 3D scaffold-based model of the bovine endometrium structurally robust for long term-culture. We developed a multicellular model containing both endometrial epithelial and stromal cells. Epithelial cells organized to form a luminal-like epithelial layer on the surface of the scaffold. Stromal cells produced their own extracellular matrix forming a stable subepithelial compartment that physiologically resembles the normal endometrium. Both cell types released prostaglandin E and prostaglandin F following a treatment with oxytocin and arachidonic acid. Additionally signal pathways mediating oxytocin and arachidonic acid stimulation of prostaglandin synthesis were analyzed by real time PCR (RT-PCR). Oxytocin receptor (OXTR), prostaglandin E receptor 2 (EP2), prostaglandin E receptor 4 (EP4), prostaglandin F receptor (PTGFR), prostaglandin E synthase (PTGES), PGF-synthase (PGFS) and prostaglandin-endoperoxide synthase 2 (COX-2) expression was detected in both control and treatment groups, however, only significant changes in abundance of OXTR mRNA transcripts were found. The results obtained by this study are a step forward in bovine in vitro culture technology. This 3D scaffold-based model provides a platform to study regulatory mechanisms involved in endometrial physiology and can set the basis for a broader tool for designing and testing novel therapeutic strategies for recurrent uterine pathologies.
Topics: Female; Animals; Cattle; Oxytocin; Arachidonic Acid; Endometrium; Dinoprostone; Prostaglandin-E Synthases
PubMed: 37154859
DOI: 10.1007/s11259-023-10130-0 -
Cell Communication and Signaling : CCS Aug 2023Extracellular vesicles (EVs) are membrane-coated nanoparticles secreted by almost all cell types in living organisms. EVs, as paracrine mediators, are involved in...
BACKGROUND
Extracellular vesicles (EVs) are membrane-coated nanoparticles secreted by almost all cell types in living organisms. EVs, as paracrine mediators, are involved in intercellular communication, immune response, and several reproductive events, including the maintenance of pregnancy. Using a domestic animal model (Sus scrofa) with an epitheliochorial, superficial type of placentation, we focused on EV biogenesis pathway at the embryo-maternal interface, when the embryonic signaling occurs for maternal recognition and the maintenance of pregnancy.
RESULTS
Transmission electron microscopy was used during early pregnancy to visualize EVs and apocrine and/or merocrine pathways of secretion. Immunofluorescent staining localized proteins responsible for EV biogenesis and cell polarization at the embryo-maternal interface. The expression profiles of genes involved in biogenesis and the secretion of EVs pointed to the possible modulation of endometrial expression by embryonic signals. Further in vitro studies showed that factors of embryonic origin can regulate the expression of the ESCRT-II complex and EV trafficking within endometrial luminal epithelial cells. Moreover, miRNA-mediated rapid negative regulation of gene expression was abolished by delivered embryonic signals.
CONCLUSIONS
Our findings demonstrated that embryonic signals are potent modulators of ESCRT-dependent EV-mediated secretory activity of the endometrium during the critical stages of early pregnancy. Video Abstract.
Topics: Animals; Female; Pregnancy; Biological Transport; Cell Communication; Endosomes; Extracellular Vesicles; Endosomal Sorting Complexes Required for Transport
PubMed: 37596609
DOI: 10.1186/s12964-023-01221-1 -
Cancer Research Communications Aug 2023While the role of prostaglandin E2 (PGE2) in promoting malignant progression is well established, how to optimally block the activity of PGE2 signaling remains to be...
UNLABELLED
While the role of prostaglandin E2 (PGE2) in promoting malignant progression is well established, how to optimally block the activity of PGE2 signaling remains to be demonstrated. Clinical trials with prostaglandin pathway targeted agents have shown activity but without sufficient significance or dose-limiting toxicities that have prevented approval. PGE2 signals through four receptors (EP1-4) to modulate tumor progression. EP2 and EP4 signaling exacerbates tumor pathology and is immunosuppressive through potentiating cAMP production. EP1 and EP3 signaling has the opposite effect through increasing IP3 and decreasing cAMP. Using available small-molecule antagonists of single EP receptors, the cyclooxygenase-2 (COX-2) inhibitor celecoxib, or a novel dual EP2/EP4 antagonist generated in this investigation, we tested which approach to block PGE2 signaling optimally restored immunologic activity in mouse and human immune cells and antitumor activity in syngeneic, spontaneous, and xenograft tumor models. We found that dual antagonism of EP2 and EP4 together significantly enhanced the activation of PGE2-suppressed mouse and human monocytes and CD8 T cells as compared with single EP antagonists. CD8 T-cell activation was dampened by single EP1 and EP3 antagonists. Dual EP2/EP4 PGE2 receptor antagonists increased tumor microenvironment lymphocyte infiltration and significantly reduced disease burden in multiple tumor models, including in the adenomatous polyposis coli (APC) spontaneous colorectal tumor model, compared with celecoxib. These results support a hypothesis that redundancy of EP2 and EP4 receptor signaling necessitates a therapeutic strategy of dual blockade of EP2 and EP4. Here we describe TPST-1495, a first-in-class orally available small-molecule dual EP2/EP4 antagonist.
SIGNIFICANCE
Prostaglandin (PGE2) drives tumor progression but the pathway has not been effectively drugged. We demonstrate significantly enhanced immunologic potency and antitumor activity through blockade of EP2 and EP4 PGE2 receptor signaling together with a single molecule.
Topics: Humans; Animals; Mice; Prostaglandins; Dinoprostone; Receptors, Prostaglandin E, EP2 Subtype; Celecoxib; CD8-Positive T-Lymphocytes; Receptors, Prostaglandin E, EP4 Subtype; Cyclooxygenase 2 Inhibitors; Neoplasms; Tumor Microenvironment
PubMed: 37559947
DOI: 10.1158/2767-9764.CRC-23-0249 -
Communications Biology Nov 2023The ketogenic diet (KD) has demonstrated benefits in numerous clinical studies and animal models of disease in modulating the immune response and promoting a systemic...
The ketogenic diet (KD) has demonstrated benefits in numerous clinical studies and animal models of disease in modulating the immune response and promoting a systemic anti-inflammatory state. Here we investigate the effects of a KD on systemic toxicity in mice following SARS-CoV-2 infection. Our data indicate that under KD, SARS-CoV-2 reduces weight loss with overall improved animal survival. Muted multi-organ transcriptional reprogramming and metabolism rewiring suggest that a KD initiates and mitigates systemic changes induced by the virus. We observed reduced metalloproteases and increased inflammatory homeostatic protein transcription in the heart, with decreased serum pro-inflammatory cytokines (i.e., TNF-α, IL-15, IL-22, G-CSF, M-CSF, MCP-1), metabolic markers of inflammation (i.e., kynurenine/tryptophane ratio), and inflammatory prostaglandins, indicative of reduced systemic inflammation in animals infected under a KD. Taken together, these data suggest that a KD can alter the transcriptional and metabolic response in animals following SARS-CoV-2 infection with improved mice health, reduced inflammation, and restored amino acid, nucleotide, lipid, and energy currency metabolism.
Topics: Mice; Animals; SARS-CoV-2; Diet, Ketogenic; COVID-19; Inflammation; Cytokines
PubMed: 37923961
DOI: 10.1038/s42003-023-05478-7 -
Cell Reports Mar 2024Prostaglandin F (PGF) and thromboxane A (TXA) are endogenous arachidonic acid metabolites, modulating diverse physiological processes including inflammation and...
Prostaglandin F (PGF) and thromboxane A (TXA) are endogenous arachidonic acid metabolites, modulating diverse physiological processes including inflammation and cardiovascular homeostasis through activating PGF receptor (FP) and TXA receptor (TP). Ligands targeting FP and TP have demonstrated efficacy in treating conditions like glaucoma and cardiovascular diseases in humans, as well as reproductive-related diseases in animals. Here, we present five cryoelectron microscopy structures illustrating FP and TP in complex with G and bound to PGF (endogenous ligand), latanoprost acid (a clinical drug), and two other synthetic agonists. Combined with mutational and functional studies, these structures reveal not only structural features for the specific recognition of endogenous ligands and attainment of receptor selectivity of FP and TP but also the common mechanisms of receptor activation and G protein coupling. The findings may enrich our knowledge of ligand recognition and signal transduction of the prostanoid receptor family and facilitate rational ligand design toward these two receptors.
Topics: Humans; Animals; Ligands; Cryoelectron Microscopy; Receptors, Prostaglandin; Signal Transduction; Prostaglandins
PubMed: 38446662
DOI: 10.1016/j.celrep.2024.113893 -
Development (Cambridge, England) Oct 2023Lipid droplets (LDs), crucial regulators of lipid metabolism, accumulate during oocyte development. However, their roles in fertility remain largely unknown. During...
Lipid droplets (LDs), crucial regulators of lipid metabolism, accumulate during oocyte development. However, their roles in fertility remain largely unknown. During Drosophila oogenesis, LD accumulation coincides with the actin remodeling necessary for follicle development. Loss of the LD-associated Adipose Triglyceride Lipase (ATGL) disrupts both actin bundle formation and cortical actin integrity, an unusual phenotype also seen when the prostaglandin (PG) synthase Pxt is missing. Dominant genetic interactions and PG treatment of follicles indicate that ATGL acts upstream of Pxt to regulate actin remodeling. Our data suggest that ATGL releases arachidonic acid (AA) from LDs to serve as the substrate for PG synthesis. Lipidomic analysis detects AA-containing triglycerides in ovaries, and these are increased when ATGL is lost. High levels of exogenous AA block follicle development; this is enhanced by impairing LD formation and suppressed by reducing ATGL. Together, these data support the model that AA stored in LD triglycerides is released by ATGL to drive the production of PGs, which promote the actin remodeling necessary for follicle development. We speculate that this pathway is conserved across organisms to regulate oocyte development and promote fertility.
Topics: Animals; Prostaglandins; Lipid Droplets; Actins; Adipogenesis; Drosophila; Lipase; Peroxidases; Drosophila Proteins
PubMed: 37306387
DOI: 10.1242/dev.201516 -
American Journal of Respiratory Cell... Nov 2023Prostaglandin E2 imparts diverse physiological effects on multiple airway cells through its actions on four distinct E-type prostanoid (EP) receptor subtypes (EP1-EP4)....
Prostaglandin E2 imparts diverse physiological effects on multiple airway cells through its actions on four distinct E-type prostanoid (EP) receptor subtypes (EP1-EP4). Gs-coupled EP2 and EP4 receptors are expressed on airway smooth muscle (ASM), yet their capacity to regulate the ASM contractile state remains subject to debate. We used EP2 and EP4 subtype-specific agonists (ONO-259 and ONO-329, respectively) in cell- and tissue-based models of human ASM contraction-magnetic twisting cytometry (MTC), and precision-cut lung slices (PCLSs), respectively-to study the EP2 and EP4 regulation of ASM contraction and signaling under conditions of histamine or methacholine (MCh) stimulation. ONO-329 was superior (<0.05) to ONO-259 in relaxing MCh-contracted PCLSs (log half maximal effective concentration [logEC]: 4.9 × 10 vs. 2.2 × 10; maximal bronchodilation ± SE, 35 ± 2% vs. 15 ± 2%). However, ONO-259 and ONO-329 were similarly efficacious in relaxing histamine-contracted PCLSs. Similar differential effects were observed in MTC studies. Signaling analyses revealed only modest differences in ONO-329- and ONO-259-induced phosphorylation of the protein kinase A substrates VASP and HSP20, with concomitant stimulation with MCh or histamine. Conversely, ONO-259 failed to inhibit MCh-induced phosphorylation of the regulatory myosin light chain (pMLC20) and the F-actin/G-actin ratio (F/G-actin ratio) while effectively inhibiting their induction by histamine. ONO-329 was effective in reversing induced pMLC20 and the F/G-actin ratio with both MCh and histamine. Thus, the contractile-agonist-dependent differential effects are not explained by changes in the global levels of phosphorylated protein kinase A substrates but are reflected in the regulation of pMLC20 (cross-bridge cycling) and F/G-actin ratio (actin cytoskeleton integrity, force transmission), implicating a role for compartmentalized signaling involving muscarinic, histamine, and EP receptor subtypes.
Topics: Humans; Receptors, Prostaglandin E, EP2 Subtype; Actins; Histamine; Receptors, Prostaglandin E, EP4 Subtype; Dinoprostone; Muscle, Smooth; Lung; Cyclic AMP-Dependent Protein Kinases
PubMed: 37523713
DOI: 10.1165/rcmb.2022-0445OC