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Ageing is characterized by the development of persistent pro-inflammatory responses that contribute to atherosclerosis, metabolic syndrome, cancer and frailty 1 – 3 . The ageing brain is also vulnerable to inflammation, as demonstrated by the high prevalence of age-associated cognitive decline and Alzheimer’s disease 4 – 6 . Systemically, circulating pro-inflammatory factors can promote cognitive decline 7 , 8 , and in the brain, microglia lose the ability to clear misfolded proteins that are associated with neurodegeneration 9 , 10 . However, the underlying mechanisms that initiate and sustain maladaptive inflammation with ageing are not well defined. Here we show that in ageing mice myeloid cell bioenergetics are suppressed in response to increased signalling by the lipid messenger prostaglandin E 2 (PGE 2 ), a major modulator of inflammation 11 . In ageing macrophages and microglia, PGE 2 signalling through its EP2 receptor promotes the sequestration of glucose into glycogen, reducing glucose flux and mitochondrial respiration. This energy-deficient state, which drives maladaptive pro-inflammatory responses, is further augmented by a dependence of aged myeloid cells on glucose as a principal fuel source. In aged mice, inhibition of myeloid EP2 signalling rejuvenates cellular bioenergetics, systemic and brain inflammatory states, hippocampal synaptic plasticity and spatial memory. Moreover, blockade of peripheral myeloid EP2 signalling is sufficient to restore cognition in aged mice. Our study suggests that cognitive ageing is not a static or irrevocable condition but can be reversed by reprogramming myeloid glucose metabolism to restore youthful immune functions. In aged mice, inhibition of prostaglandin E 2 (PGE 2 ) signalling through its receptor EP2 improves cellular bioenergetics, reduces inflammatory responses and restores hippocampal plasticity to youthful levels, resulting in an improvement in spatial memory and cognition.

Prostaglandin induced signalling is involved in different cancers. As previously described, the EP3 receptor expression decreases with increasing stage of cervical intraepithelial lesions (CIN). In addition, in cervical cancer EP3 is an independent prognosticator for overall survival and correlates with FIGO stages. Currently the role of Prostaglandin 2 receptor 2 (EP2) in CIN is unknown. The aim of this study was to analyse the expression of EP2 for potential prognostic value for patients with cervical dysplasia. EP2 expression was analysed by immunohistochemistry in 33 patient samples (CIN1–3) using the immune-reactivity scoring system (IRS). Expression levels were correlated with clinical outcome to analyse prognostic relevance in patients with CIN2. Data analysis was performed using non parametric Kruskal–Wallis and Spearman rank sum test. Cytoplasmic expression levels of EP2 correlated significantly (p < 0.001) with different grades of cervical dysplasia. Median EP2-IRS in CIN1 was 2 (n = 8), 3 in CIN2 (n = 9) and 6 in CIN3 (n = 16). Comparing regressive (n = 3, median IRS = 2) to progressive (n = 6, median IRS = 4) CIN2 cases the median IRS differed significantly (p = 0.017). Staining intensity (p = 0.009) and IRS (p = 0.005) of EP2 and EP3 correlate inversely. EP2 expression level significantly increases with higher grade of CIN and could qualify as a potential prognostic marker for the regressive or progressive course in CIN2 lesions. These findings emphasize the significant role of PGE2 signalling in CIN and could help to identify targets for future therapies.

Prostaglandin receptors are pharmacologically validated targets with implications in several medical indications, including glaucoma, cardiac cyanotic disease, pulmonary hypertension, oncology, and various rare diseases. In this study, we developed a ligand-based machine learning (ML) model to classify chemical compounds as either active or inactive against the prostaglandin receptor EP2. From an initial set of 1,826 descriptors, 20 were selected to train random forest algorithms, yielding an area under the curve score (AUC) of > 0.8 for compound classification in the test set. Our resulting ML classifier showed an overall accuracy of 88.9% towards newly experimentally tested EP2 ligands. This adaptable and tractable workflow can be extended to other EP receptors and possibly other similar targets.

Background Cyclooxygenase-2 (COX-2) is induced under inflammatory conditions, and prostaglandin E 2 (PGE 2 ) is one of the products of COX activity. PGE 2 has pleiotropic actions depending on the activation of specific E-type prostanoid EP1-4 receptors. We investigated the involvement of PGE 2 and EP receptors in glial activation in response to an inflammatory challenge induced by LPS. Methods Cultures of mouse microglia or astroglia cells were treated with LPS in the presence or absence of COX-2 inhibitors, and the production of PGE 2 was measured by ELISA. Cells were treated with PGE 2 , and the effect on LPS-induced expression of TNF-α messenger RNA (mRNA) and protein was studied in the presence or absence of drug antagonists of the four EP receptors. EP receptor expression and the effects of EP2 and EP4 agonists and antagonists were studied at different time points after LPS. Results PGE 2 production after LPS was COX-2-dependent. PGE 2 reduced the glial production of TNF-α after LPS. Microglia expressed higher levels of EP4 and EP2 mRNA than astroglia. Activation of EP4 or EP2 receptors with selective drug agonists attenuated LPS-induced TNF-α in microglia. However, only antagonizing EP4 prevented the PGE 2 effect demonstrating that EP4 was the main target of PGE 2 in naïve microglia. Moreover, the relative expression of EP receptors changed during the course of classical microglial activation since EP4 expression was strongly depressed while EP2 increased 24 h after LPS and was detected in nuclear/peri-nuclear locations. EP2 regulated the expression of iNOS, NADPH oxidase-2, and vascular endothelial growth factor. NADPH oxidase-2 and iNOS activities require the oxidation of NADPH, and the pentose phosphate pathway is a main source of NADPH. LPS increased the mRNA expression of the rate-limiting enzyme of the pentose pathway glucose-6-phosphate dehydrogenase, and EP2 activity was involved in this effect. Conclusions These results show that while selective activation of EP4 or EP2 exerts anti-inflammatory actions, EP4 is the main target of PGE 2 in naïve microglia. The level of EP receptor expression changes from naïve to primed microglia where the COX-2/PGE 2 /EP2 axis modulates important adaptive metabolic changes.

Patients with cirrhosis are susceptible to infection, but the mechanisms underlying this immunosuppression remain unclear. Derek W. Gilroy and colleagues show that plasma prostaglandin E 2 (PGE 2 ) is elevated in these patients and in mouse models of liver injury and suppresses TNF-α release from macrophages. Albumin, which binds to PGE 2 and reduces its bioavailability, is reduced in the plasma of a subset of cirrhosis patients. Administration of albumin partially reverses the immunosuppression observed in vitro and restores bacterial killing in mouse models, suggesting that future studies are warranted on the use of albumin to prevent infection in a subset of patients with cirrhosis. Liver disease is one of the leading causes of death worldwide 1 . Patients with cirrhosis display an increased predisposition to and mortality from infection due to multimodal defects in the innate immune system 2 , 3 , 4 ; however, the causative mechanism has remained elusive. We present evidence that the cyclooxygenase (COX)-derived eicosanoid prostaglandin E 2 (PGE 2 ) drives cirrhosis-associated immunosuppression. We observed elevated circulating concentrations (more than seven times as high as in healthy volunteers) of PGE 2 in patients with acute decompensation of cirrhosis. Plasma from these and patients with end-stage liver disease (ESLD) suppressed macrophage proinflammatory cytokine secretion and bacterial killing in vitro in a PGE 2 -dependent manner via the prostanoid type E receptor-2 (EP2), effects not seen with plasma from patients with stable cirrhosis (Child-Pugh score grade A). Albumin, which reduces PGE 2 bioavailability, was decreased in the serum of patients with acute decompensation or ESLD (<30 mg/dl) and appears to have a role in modulating PGE 2 -mediated immune dysfunction. In vivo administration of human albumin solution to these patients significantly improved the plasma-induced impairment of macrophage proinflammatory cytokine production in vitro . Two mouse models of liver injury (bile duct ligation and carbon tetrachloride) also exhibited elevated PGE 2 , reduced circulating albumin concentrations and EP2-mediated immunosuppression. Treatment with COX inhibitors or albumin restored immune competence and survival following infection with group B Streptococcus . Taken together, human albumin solution infusions may be used to reduce circulating PGE 2 levels, attenuating immune suppression and reducing the risk of infection in patients with acutely decompensated cirrhosis or ESLD.

Purpose Omidenepag isopropyl (OMDI) is the prodrug of omidenepag, a selective, non-prostaglandin, prostanoid EP2 receptor agonist, which has been shown to lower intraocular pressure (IOP) in patients with glaucoma and ocular hypertension (OHT). This study evaluated the efficacy and safety of OMDI ophthalmic solution 0.002% in patients with primary open-angle glaucoma or OHT who were non-/low responders to latanoprost. Study design Open-label, multicenter, Phase 3 study (NCT02822742). Methods Following 1–4-week washout, patients were treated with latanoprost ophthalmic solution 0.005% during an 8-week run-in period. Patients with ≤15% IOP reduction at the end of the run-in (indicating non-/low response) received OMDI 0.002% (one drop once daily for 4 weeks). The primary endpoint was the change from baseline in mean diurnal IOP at Week 4. Results In total, 26 patients were treated with OMDI; two withdrew owing to lack of efficacy. The mean diurnal IOP at baseline (end of latanoprost run-in) was 23.1 mmHg (7.6% IOP reduction from end of washout) indicating non-/low response to latanoprost. After 4 weeks of OMDI treatment, mean diurnal IOP was significantly reduced from baseline (−2.99 mmHg; P  < 0.0001). No serious adverse events were reported. Adverse events occurred in five patients (19.2%); adverse drug reactions (anterior chamber cell, conjunctival hyperemia, and erythema of eyelid) occurred in two patients (7.7%) and were mild in severity. Conclusions In this study, OMDI 0.002% demonstrated a clinically significant reduction in IOP and was well tolerated in patients with primary open-angle glaucoma and OHT who were non-/low responders to latanoprost.

Recurrent, rapidly growing nasal polyps are hallmarks of aspirin-exacerbated respiratory disease (AERD), although the mechanisms of polyp growth have not been identified. Fibroblasts are intimately involved in tissue remodeling, and the growth of fibroblasts is suppressed by prostaglandin E2 (PGE2), which elicits antiproliferative effects mediated through the E prostanoid (EP)2 receptor. We now report that cultured fibroblasts from the nasal polyps of subjects with AERD resist this antiproliferative effect. Fibroblasts from polyps of subjects with AERD resisted the antiproliferative actions of PGE2 and a selective EP2 agonist (P < 0.0001 at 1 μM) compared with nasal fibroblasts from aspirin-tolerant control subjects undergoing polypectomy or from healthy control subjects undergoing concha bullosa resections. Cell surface expression of the EP2 receptor protein was lower in fibroblasts from subjects with AERD than in fibroblasts from healthy control subjects and aspirin-tolerant subjects (P < 0.01 for both). Treatment of the fibroblasts with trichostatin A, a histone deacetylase inhibitor, significantly increased EP2 receptor mRNA in fibroblasts from AERD and aspirin-tolerant subjects but had no effect on cyclooxygenase-2, EP4, and microsomal PGE synthase 1 (mPGES-1) mRNA levels. Histone acetylation (H3K27ac) at the EP2 promoter correlated strongly with baseline EP2 mRNA (r = 0.80; P < 0.01). These studies suggest that the EP2 promotor is under epigenetic control, and one explanation for PGE2 resistance in AERD is an epigenetically mediated reduction of EP2 receptor expression, which could contribute to the refractory nasal polyposis typically observed in this syndrome.

Prostaglandin-E2 (PGE2), an important mediator of inflammation, achieves its functions via four different G protein–coupled receptors (EP1, EP2, EP3, and EP4). We previously demonstrated that the EP2 receptor plays a proinflammatory and neurodegenerative role after status epilepticus (SE). We recently developed TG8-260 as a second-generation highly potent and selective EP2 antagonist. Here, we investigate whether TG8-260 is anti-inflammatory and combats neuropathology caused by pilocarpine-induced SE in rats. Adult male Sprague–Dawley rats were injected subcutaneously with pilocarpine (380–400 mg/kg) to induce SE. Following 60 min of SE, the rats were administered three doses of TG8-260 or vehicle and were allowed to recover. Neurodegeneration, neuroinflammation, gliosis, and blood–brain barrier (BBB) integrity were examined 4 days after SE. The results confirmed that pilocarpine-induced SE results in hippocampal neurodegeneration and a robust inflammatory response that persists days after SE. Furthermore, inhibition of the EP2 receptor by TG8-260 administered beginning 2 h after SE significantly reduced hippocampal neuroinflammation and gliosis but, in distinction to the earlier generation EP2 antagonist, did not mitigate neuronal injury or BBB breakdown. Thus, attenuation of neuroinflammation and gliosis is a common feature of EP2 inhibition following SE.

Duchenne muscular dystrophy (DMD) is a severe genetic muscle disease occurring due to mutations of the dystrophin gene. There is no cure for DMD. Using a dystrophin−/−utrophin−/− (DKO-Hom) mouse model, we investigated the PGE2/EP2 pathway in the pathogenesis of dystrophic muscle and its potential as a therapeutic target. We found that Ep2, Ep4, Cox-2, 15-Pgdh mRNA, and PGE2 were significantly increased in DKO-Hom mice compared to wild-type (WT) mice. The EP2 and EP4 receptors were mainly expressed in CD68+ macrophages and were significantly increased in the muscle tissues of both dystrophin−/− (mdx) and DKO-Hom mice compared to WT mice. Osteogenic and osteoclastogenic gene expression in skeletal muscle also increased in DKO-Hom mice, which correlates with severe muscle heterotopic ossification (HO). Treatment of DKO-Hom mice with the EP2 antagonist PF04418948 for 2 weeks increased body weight and reduced HO and muscle pathology by decreasing both total macrophages (CD68+) and senescent macrophages (CD68+P21+), while increasing endothelial cells (CD31+). PF04418948 also increased bone volume/total volume (BV/TV), the trabecular thickness (Tb.Th) of the tibia trabecular bone, and the cortical bone thickness of both the femur and tibia without affecting spine trabecular bone microarchitecture. In summary, our results indicate that targeting EP2 improves muscle pathology and improves bone mass in DKO mice.

Background: Non-steroidal anti-inflammatory drugs inhibit the activity of cyclooxygenases (COXs), and their usage reduces the risks associated with prostate cancer. Celecoxib is a selective COX-2 inhibitor and reported to prevent the progression of prostate cancer. However, the mechanisms involved remain unclear. In this study, we investigated the suppression of prostate cancer growth by celecoxib and elucidated the biological relevance of the inhibited pathway in prostate cancer cell lines. Methods: Western blotting, quantitative real-time PCR and cell proliferation assay were used to resolve the mechanism of celecoxib in prostate cancer cell line PC3, LNCaP and their derivatives. Results: Celecoxib induced apoptosis and downregulated EP2, CREB and androgen receptor (AR). Moreover, EP2 antagonist downregulated CREB as well as COX-2 and AR, resulting in the suppression of cell proliferation. Furthermore, EP2 and CREB knockdown induced AR downregulation, indicating that AR suppression by celecoxib is mediated by EP2/CREB signaling. Conclusions: Celecoxib exerts antitumor activity through EP2 signaling regulating AR and COX-2 expression. Furthermore, in addition to celecoxib, therapeutics targeting EP2 may also be promising against prostate cancers.