Search

Regulatory T (Treg) cells are essential for control of inflammatory processes by suppressing effector T-cell functions. The actions of PGE2 on the development and function of Treg cells, particularly under inflammatory conditions, are debated. In this study, we employed pharmacological and genetic approaches to examine whether PGE2 had a direct action on T cells to modulate de novo differentiation of Treg cells. We found that TGF-β-induced Foxp3 expression and iTreg cell differentiation in vitro is markedly inhibited by PGE2 , which was mediated by the receptors EP2 and EP4. Mechanistically, PGE2 -EP2/EP4 signalling interrupts TGF-β signalling during iTreg differentiation. Moreover, EP4 deficiency in T cells impaired iTreg cell differentiation in vivo. Thus, our results demonstrate that PGE2 negatively regulates iTreg cell differentiation through a direct action on T cells, highlighting the potential for selectively targeting the PGE2 -EP2/EP4 pathway to control T cell-mediated inflammation.

BACKGROUND: Group 2 innate lymphoid cells (ILC2s) play a critical role in asthma pathogenesis. Non-steroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (NERD) is associated with reduced signaling via EP2, a receptor for prostaglandin E 2 (PGE 2 ). However, the respective roles for the PGE 2 receptors EP2 and EP4 (both share same downstream signaling) in the regulation of lung ILC2 responses has yet been deciphered. METHODS: The roles of PGE 2 receptors EP2 and EP4 on ILC2-mediated lung inflammation were investigated using genetically modified mouse lines and pharmacological approaches in IL-33-induced lung allergy model. The effects of PGE 2 receptors and downstream signals on ILC2 metabolic activation and effector function were examined using in vitro cell cultures. RESULTS: Deficiency of EP2 rather than EP4 augments IL-33-induced mouse lung ILC2 responses and eosinophilic inflammation in vivo. In contrast, exogenous agonism of EP4 and EP2 or inhibition of phosphodiesterase markedly restricts IL-33-induced lung ILC2 responses. Mechanistically, PGE 2 directly suppresses IL-33-dependent ILC2 activation through the EP2/EP4-cAMP pathway, which downregulates STAT5 and MYC pathway gene expression and ILC2 energy metabolism. Blocking glycolysis diminishes IL-33-dependent ILC2 responses in mice where endogenous PG synthesis or EP2 signaling is blocked but not in mice with intact PGE 2 -EP2 signaling. CONCLUSION: We have defined a mechanism for optimal suppression of mouse lung ILC2 responses by endogenous PGE 2 -EP2 signaling which underpins the clinical findings of defective EP2 signaling in patients with NERD. Our findings also indicate that exogenously targeting the PGE 2 -EP4-cAMP and energy metabolic pathways may provide novel opportunities for treating the ILC2-initiated lung inflammation in asthma and NERD.

Group 2 innate lymphoid cells (ILC2s) play a critical role in asthma pathogenesis. Non-steroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (NERD) is associated with reduced signaling via EP2, a receptor for prostaglandin EThe roles of PGEDeficiency of EP2 rather than EP4 augments IL-33-induced mouse lung ILC2 responses and eosinophilic inflammation in vivo. In contrast, exogenous agonism of EP4 and EP2 or inhibition of phosphodiesterase markedly restricts IL-33-induced lung ILC2 responses. Mechanistically, PGEWe have defined a mechanism for optimal suppression of mouse lung ILC2 responses by endogenous PGE

Background: Group 2 innate lymphoid cells (ILC2s) play a critical role in asthma pathogenesis. Non-steroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (NERD) is associated with reduced signaling via EP2, a receptor for prostaglandin E (PGE ). However, the respective roles for the PGE receptors EP2 and EP4 (both share same downstream signaling) in the regulation of lung ILC2 responses has yet been deciphered. Methods: The roles of PGE receptors EP2 and EP4 on ILC2-mediated lung inflammation were investigated using genetically modified mouse lines and pharmacological approaches in IL-33- and Alternaria alternata (A.A.)-induced lung allergy models. The effects of PGE receptors and downstream signals on ILC2 metabolic activation and effector function were examined using in vitro cell cultures. Results: Deficiency of EP2 rather than EP4 augments IL-33-induced lung ILC2 responses and eosinophilic inflammation in vivo. In contrast, exogenous agonism of EP4 but not EP2 markedly restricts IL-33- and Alternaria alternata-induced lung ILC2 responses and eosinophilic inflammation. Mechanistically, PGE directly suppresses IL-33-dependent ILC2 activation through the EP2/EP4-cAMP pathway, which downregulates STAT5 and MYC pathway gene expression and ILC2 energy metabolism. Blocking glycolysis diminishes IL-33-dependent ILC2 responses in mice lacking endogenous PG synthesis but not in PG-competent mice. Conclusion: We have defined a mechanism for optimal suppression of lung ILC2 responses by endogenous PGE -EP2 signaling which underpins the clinical findings of defective EP2 signaling in patients with NERD. Our findings also indicate that exogenously targeting the PGE -EP4-cAMP and energy metabolic pathways may provide novel opportunities for treating ILC2-initiated lung inflammation in asthma and NERD.

Group 2 innate lymphoid cells (ILC2s) play a critical role in asthma pathogenesis. Non-steroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (NERD) is associated with reduced signaling via EP2, a receptor for prostaglandin E2 (PGE2). However, the respective roles for the PGE2 receptors EP2 and EP4 (both share same downstream signaling) in the regulation of lung ILC2 responses has yet been deciphered. Here, we find that deficiency of EP2 rather than EP4 augments IL-33-induced lung ILC2 responses and eosinophilic inflammation in vivo. In contrast, exogenous agonism of EP4 but not EP2 markedly restricts IL-33- and Alternaria alternata-induced lung ILC2 responses and eosinophilic inflammation. Mechanistically, PGE2 directly suppresses IL-33-dependent ILC2 activation through the EP2/EP4-cAMP pathway, which downregulates STAT5 and MYC pathway gene expression and ILC2 energy metabolism. Blocking glycolysis diminishes IL-33-dependent ILC2 responses in mice lacking endogenous PG synthesis but not in PG-competent mice. Together, we have defined a mechanism for optimal suppression of lung ILC2 responses by endogenous PGE2-EP2 signaling which underpins the clinical findings of defective EP2 signaling in patients with NERD. Our findings also indicate that exogenously targeting the PGE2-EP4-cAMP and energy metabolic pathways may provide novel opportunities for treating ILC2-initiated lung inflammation in asthma and NERD.Graphical abstractSchematic of potential roles for activation of EP2 and EP4 by endogenous versus exogenous ligands in regulation of lung ILC2 immune responses. Endogenous PGE2 in the lung preferentially activates EP2 rather than EP4 to inhibit ILC2 responses and eosinophilic inflammation, and ablation of EP2 enhances lung ILC2 responses. Conversely, lung ILC2 responses are not altered by EP4 deficiency. However, they are markedly inhibited by EP4 agonism but not EP2 agonism. Mechanistically, PGE2-EP2/EP4 signaling activates the cAMP pathway which inhibits ILC2 energy metabolism, possibly through interruption of NF-κB (reported in Nagashima H, et al. Immunity 2019;51:682-695) and STAT5 signaling, leading to decline of ILC2 survival, proliferation and type 2 cytokine production.

Regulatory T (Treg) cells are essential for control of inflammatory processes by suppressing effector T‐cell functions. The actions of PGE2 on the development and function of Treg cells, particularly under inflammatory conditions, are debated. In this study, we employed pharmacological and genetic approaches to examine whether PGE2 had a direct action on T cells to modulate de novo differentiation of Treg cells. We found that TGF‐β‐induced Foxp3 expression and iTreg cell differentiation in vitro is markedly inhibited by PGE2, which was mediated by the receptors EP2 and EP4. Mechanistically, PGE2‐EP2/EP4 signalling interrupts TGF‐β signalling during iTreg differentiation. Moreover, EP4 deficiency in T cells impaired iTreg cell differentiation in vivo. Thus, our results demonstrate that PGE2 negatively regulates iTreg cell differentiation through a direct action on T cells, highlighting the potential for selectively targeting the PGE2‐EP2/EP4 pathway to control T cell‐mediated inflammation., We have found that the development of inducible Treg cells is inhibited by PGE2 through its receptors EP2/EP4 and direct down‐regulation of TGF‐β signalling. Our results suggest a role for the PGE2‐EP2/EP4 pathway in T cell‐mediated inflammation.

Background and PurposeRegulatory T (Treg) cells are essential for control of inflammatory processes by suppressing Th1 and Th17 cells. The bioactive lipid mediator prostaglandin E2 (PGE2) promotes inflammatory Th1 and Th17 cells and exacerbates T cell-mediated autoimmune diseases. However, the actions of PGE2 on the development and function of Treg cells, particularly under inflammatory conditions, are debated. In this study, we examined whether PGE2 had a direct action on T cells to modulate de novo differentiation of Treg cells.Experimental ApproachWe employed an in vitro T cell culture system of TGF-β-dependent Treg induction from naïve T cells. PGE2 and selective agonists for its receptors, and other small molecular inhibitors were used. Mice with specific lack of EP4 receptors in T cells were used to assess Treg cell differentiation in vivo. Human peripheral blood T cells from healthy individuals were used to induce differentiation of inducible Treg cells.Key ResultsTGF-β-induced Foxp3 expression and Treg cell differentiation in vitro was markedly inhibited by PGE2, which was due to interrupting TGF-β signalling. EP2 or EP4 agonism mimicked suppression of Foxp3 expression in WT T cells, but not in T cells deficient in EP2 or EP4, respectively. Moreover, deficiency of EP4 in T cells impaired iTreg cell differentiation in vivo. PGE2 also appeared to inhibit the conversion of human iTreg cells.Conclusion and ImplicationsOur results show a direct, negative regulation of iTreg cell differentiation by PGE2, highlighting the potential for selectively targeting the PGE2-EP2/EP4 pathway to control T cell-mediated inflammation.What is already knownPGE2 promotes inflammatory Th1 and Th17 cells and facilitates T cell-mediated immune inflammation, but the action of PGE2 on Treg cells is debated.What does this study addPGE2 directly acts on T cells to inhibit inducible Treg cell differentiation in vitro and in vivo through its receptors EP2 and EP4 and by antagonising TGF-β signalling.What is the clinical significanceTherapeutically blocking the EP4 receptor may be beneficial for management of T cell-mediated autoimmune inflammation.

PGE2 inhibits Tregs and promotes intestinal inflammation through actions on mononuclear phagocytes and the gut microbiota., The gut microbiota fundamentally regulates intestinal homeostasis and disease partially through mechanisms that involve modulation of regulatory T cells (Tregs), yet how the microbiota-Treg cross-talk is physiologically controlled is incompletely defined. Here, we report that prostaglandin E2 (PGE2), a well-known mediator of inflammation, inhibits mucosal Tregs in a manner depending on the gut microbiota. PGE2 through its receptor EP4 diminishes Treg-favorable commensal microbiota. Transfer of the gut microbiota that was modified by PGE2-EP4 signaling modulates mucosal Treg responses and exacerbates intestinal inflammation. Mechanistically, PGE2-modified microbiota regulates intestinal mononuclear phagocytes and type I interferon signaling. Depletion of mononuclear phagocytes or deficiency of type I interferon receptor diminishes PGE2-dependent Treg inhibition. Together, our findings provide emergent evidence that PGE2-mediated disruption of microbiota-Treg communication fosters intestinal inflammation.

Prostaglandins are derived from arachidonic acid metabolism through cyclooxygenase activities. Among prostaglandins (PGs), prostacyclin (PGI2) and PGE2 are strongly involved in the regulation of homeostasis and main physiologic functions. In addition, the synthesis of these two prostaglandins is significantly increased during inflammation. PGI2 and PGE2 exert their biologic actions by binding to their respective receptors, namely prostacyclin receptor (IP) and prostaglandin E2 receptor (EP) 1–4, which belong to the family of G-protein–coupled receptors. IP and EP1–4 receptors are widely distributed in the body and thus play various physiologic and pathophysiologic roles. In this review, we discuss the recent advances in studies using pharmacological approaches, genetically modified animals, and genome-wide association studies regarding the roles of IP and EP1–4 receptors in the immune, cardiovascular, nervous, gastrointestinal, respiratory, genitourinary, and musculoskeletal systems. In particular, we highlight similarities and differences between human and rodents in terms of the specific roles of IP and EP1–4 receptors and their downstream signaling pathways, functions, and activities for each biologic system. We also highlight the potential novel therapeutic benefit of targeting IP and EP1–4 receptors in several diseases based on the scientific advances, animal models, and human studies. SIGNIFICANCE STATEMENT In this review, we present an update of the pathophysiologic role of the prostacyclin receptor, prostaglandin E2 receptor (EP) 1, EP2, EP3, and EP4 receptors when activated by the two main prostaglandins, namely prostacyclin and prostaglandin E2, produced during inflammatory conditions in human and rodents. In addition, this comparison of the published results in each tissue and/or pathology should facilitate the choice of the most appropriate model for the future studies.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the novel coronavirus disease 2019 (COVID-19), a highly pathogenic and sometimes fatal respiratory disease responsible for the current 2020 global pandemic. Presently, there remains no effective vaccine or efficient treatment strategies against COVID-19. Non-steroidal anti-inflammatory drugs (NSAIDs) are medicines very widely used to alleviate fever, pain, and inflammation (common symptoms of COVID-19 patients) through effectively blocking production of prostaglandins (PGs) via inhibition of cyclooxyganase enzymes. PGs can exert either proinflammatory or anti-inflammatory effects depending on the inflammatory scenario. In this review, we survey the potential roles that NSAIDs and PGs may play during SARS-CoV-2 infection and the development and progression of COVID-19. LINKED ARTICLES: This article is part of a themed issue on The Pharmacology of COVID-19. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.21/issuetoc.

The gut microbiota fundamentally regulates intestinal homeostasis and disease partially through mechanisms that involve modulation of regulatory T cells (Tregs), yet how the microbiota-Treg crosstalk is physiologically controlled is incompletely defined. Here, we report that prostaglandin E2 (PGE2), a well-known mediator of inflammation, inhibits mucosal Tregs in a manner depending on the gut microbiota. PGE2 through its receptor EP4 diminishes Treg-favorable commensal microbiota. Transfer of the gut microbiota that was modified by PGE2-EP4 signaling modulates mucosal Treg responses and exacerbates intestinal inflammation. Mechanistically, PGE2-modified microbiota regulates intestinal mononuclear phagocytes and type I interferon signaling. Depletion of mononuclear phagocytes or deficiency of type I interferon receptor contracts PGE2-dependent Treg inhibition. Taken together, our findings provide emergent evidence that PGE2-mediated disruption of microbiota-Treg communication fosters intestinal inflammation.

International audience; This study shows that double thymidine block treatment efficiently arrests the EO771 cells in the S-phase without altering cell growth or survival. A long-term analysis of cell behavior, using 5(6)-carboxyfluorescein diacetate N-succinimidyl ester (CFSE) staining, show synchronization to be stable and consistent over time. The EO771 cell line is a medullary breast-adenocarcinoma cell line isolated from a spontaneous murine mammary tumor, and can be used to generate murine tumor implantation models. Different biological (serum or amino acid deprivation), physical (elutriation, mitotic shake-off), or chemical (colchicine, nocodazole, thymidine) treatments are widely used for cell synchronization. Of the different methods tested, the double thymidine block is the most efficient for synchronization of murine EO771 cells if a large quantity of highly synchronized cells is recommended to study functional and biochemical events occurring in specific points of cell cycle progression.

Accumulative evidence links breast cancer development to excess weight and obesity. During obesity, dysregulations of adipose tissue induce an increase in pro-inflammatory adipokine secretions, such as leptin and oestrogen secretions. Furthermore, a raise in oxidative stress, along with a decrease in antioxidant capacity, induces and maintains chronic inflammation, which creates a permissive environment for cancer development. Physical activity is recommended as a non-pharmacological therapy in both obese and cancer situations. Physical activity is associated with a moderation of acute inflammation, higher antioxidant defences and adipokine regulation, linked to a decrease of tumour-cell proliferation. However, the biological mechanisms underlying the relationship between oxidative stress, low-grade inflammation, carcinogenesis, obesity and physical activity are poorly understood. Our study is based on old, ovariectomised mice (C57BL/6J mice, 33 weeks old), fed with a high fat diet which increases adipose tissue favouring overweight and obesity, and housed in either an enriched environment, promoting physical activity and social interactions, or a standard environment constituting close to sedentary conditions. Our model of mammary carcinogenesis allowed for the exploration of tissue secretions and signalling pathway activation as well as the oxidative status in tumours to clarify the mechanisms involved in a multiple factorial analysis of the data set. The multiple factorial analysis demonstrated that the most important variables linked to moderate, spontaneous physical activity were the increase in growth factor (epithelial growth factor (EGF), hepatocyte growth factor (HGF)) and the activation of the signalling pathways (STAT3, c-jun n-terminal kinases (JNK), EKR1/2, nuclear factor-kappa B (NF-κB)) in the gastrocnemius (G). In inguinal adipose tissue, the NF-κB inflammation pathway was activated, increasing the IL-6 content. The adiponectin plasma (P) level increased and presented an inverse correlation with tumour oxidative status. Altogether, these results demonstrated that spontaneous physical activity in obesity conditions could slow down tumour growth through crosstalk between muscle, adipose tissue and tumour. A spontaneous moderate physical activity was able to modify the inter-organ exchange in a paracrine manner. The different tissues changed their signalling pathways and adipokine/cytokine secretions, such as adiponectin and leptin, resulting in a decrease in anti-oxidative response and inflammation in the tumour environment. This model showed that moderate, spontaneous physical activity suppresses tumour growth via a dialogue between the organs close to the tumour.

Nutrition en pathologie : cancer, insuffisance d’organes, réanimation, pathologies digestives…COMMUNICATIONS AFFICHEES; Introduction et but de l’étude: En situation d’obésité, les dérégulations du tissu adipeux induisent la sécrétion d’œstradiol et de leptine (pro-inflammatoire) aux dépens d'adiponectine (anti-inflammatoire), une augmentation du stress oxydant associée à une baisse des capacités anti-oxydantes favorisant un microenvironnement pro-carcinogène. L’activité physique (AP), facteur de prévention de l’obésité et des cancers, favorise une inflammation aigüe modérée, la réponse anti-oxydante et la sécrétion d’adipokines anti-inflammatoires. Les mécanismes de protection de l’AP dans le cancer mammaire sont mal connus. Le but est de caractériser le dialogue inter-organe induit par l’AP spontanée et l’impact sur la croissance tumorale dans un modèle de carcinogenèse mammaire murin en situation d’obésité.Matériel et méthodes: Des souris C57BL/6 âgées (n=10/groupe), ovariectomisées, nourries avec un régime hyper-lipidique, sont hébergées en environnement standard (ES) ou en environnement enrichi (EE) favorisant l’AP spontanée. Après 4 semaines, des cellules tumorales syngéniques EO771 sont implantées par fat-pad. Au sacrifice, l’exploration des adipokines et des cytokines a été conduite dans les organes d’intérêt (tumeur, tissu adipeux inguinal, gastrocnémien, plasma) ainsi que la caractérisation du statut oxydatif et des voies de signalisation (JNK, AKT, NFκB, p38, S6K1) de la tumeur.Résultats et Analyse statistique : L’EE entraîne une augmentation de l’AP sans modification des masses maigres et adipeuses, ni des métabolites énergétiques (triglycérides, glucose). L’analyse factorielle multiple montre que les variables expliquant les différences entre individus sont les masses adipeuses (totale, viscérale et inguinale), l’adiponectine plasmatique, les taux de leptine des tissus d’intérêt, les capacités anti-oxydantes et les voies de signalisation intra-tumorales. Les adipokines plasmatiques sont corrélées aux masses adipeuses et aux voies de signalisation tumorales. Le taux de leptine dans le gastrocnémien est corrélé avec celui de la tumeur (r²=0,57 p

Introduction et but de l’etude L’activite physique est recommandee pour limiter les effets deleteres des pathologies chroniques comme l’obesite et obtenir un effet benefique global sur la sante. Dans le cas de la carcinogenese mammaire, la pratique d’une activite physique est associee a une diminution du risque de cancer. Cependant, les mecanismes sous-jacents restent meconnus. Notre objectif est d’evaluer, dans un modele murin orthotopique de carcinogenese mammaire, l’impact de l’activite physique spontanee sur la reponse immunitaire au niveau systemique et tumoral chez des animaux nourris avec un regime hyperlipidique obesogene. Materiel et methodes Des souris femelles C57/bl6 âgees (33 semaines) ovariectomisees sont nourries avec un regime hyperlipidique (HL : 4,3 kcal/g, dont lipides 45 % AET) et placees soit en environnement standard (ES, n = 10) soit en environnement enrichi (EE, n = 10) afin de favoriser l’activite physique spontanee et les interactions sociales. Apres 4 semaines, les groupes recoivent une implantation de cellules tumorales (EO771) dans la 4e glande mammaire. Au sacrifice, un phenotypage des cellules immunocompetentes est conduit par cytometrie en flux a partir des tumeurs et des principaux tissus immunitaires (thymus, rate, ganglions…). La reponse immunitaire est interpretee en regard de la composition corporelle, de l’activite physique spontanee des animaux ainsi que de la croissance tumorale, qui sont evaluees tout au long de l’experimentation (7 semaines). Les comparaisons entre groupes sont realisees par le test de Mann–Whitney et pour les evolutions ponderales selon le test de correlation de Spearman. Resultats et analyse statistique Les organes lymphoides peripheriques (rate et ganglions inguinaux) presentent sous regime HL une hypertrophie correlee a la taille de la tumeur quel que soit le groupe (r = 0,4652, p Alors qu’une diminution de l’activite physique spontanee est observee en ES en presence de tumeur, elle est augmentee par l’EE (39 % vs 150 %, p Conclusion Dans notre modele, l’activite physique spontanee des animaux en environnement enrichi induit une modification de la migration des cellules immunitaires (LT, MDSC…) depuis les organes lymphoides secondaires vers la tumeur ainsi qu’une reduction de la croissance tumorale. Une telle pratique physique se traduit par une diminution de l’hypertrophie des organes lymphoides et une repolarisation de la reponse immunitaire anti-tumorale au niveau systemique et tumoral. Ainsi, l’activite physique spontanee induit un recrutement intra-tumoral de cellules cytotoxiques limitant la carcinogenese.

Introduction et but de l’etude L’obesite est un facteur de risque du cancer du sein apres la menopause. Elle est egalement associee a un risque accru de recidive et de mortalite du cancer initial ainsi que de developpement d’un second cancer. Les effets deleteres de l’obesite decoulent de dysregulations metaboliques, de moindres defenses immunitaires et du stress oxydant. Notre objectif est d’evaluer, dans un modele murin orthotopique de carcinogenese mammaire, l’impact d’un regime hyper lipidique obesogene sur la reponse cellulaire immunitaire au niveau systemique et tumoral. Materiel et methodes Des souris femelles C57/bl6 âgees (33 semaines) ovariectomisees ont ete nourries avec un regime standard (3,4 kcal/g, lipides pour 10 % de l’ apport energetique total, deux groupes n = 10) ou un regime hyperlipidique (4,3 kcal/g, lipides pour 45 % de l’apport energetique total, deux groupes n = 10). Apres 4 semaines, un groupe de chaque regime a recu une implantation de cellules tumorales (EO771) dans la quatrieme glande mammaire. L’evolution ponderale, la composition corporelle, l’activite physique spontanee des animaux ainsi que la croissance tumorale ont ete mesurees tout au long de l’experimentation. Au sacrifice, un phenotypage des cellules immunocompetentes a ete conduit par cytometrie en flux a partir des tumeurs et des principaux tissus immunitaires (thymus, rate, ganglions, etc.). Les comparaisons entre groupes sont realisees par le test de Mann Whitney et pour les evolutions ponderales des organes selon le test de correlation de Spearman. Resultats Le regime hyperlipidique induisait une diminution de 39 % de l’activite physique spontanee en parallele d’une augmentation de la masse grasse (30 contre 11 % d’adiposite, p = 0,01) par rapport au regime standard. Cela s’accompagnait d’un volume tumoral plus important (1114 ± 793 contre 384 ± 339 mm 3 a 16 jours, p = 0,04). Les organes lymphoides peripheriques (rate et ganglions inguinaux) presentaient une hypertrophie correlee avec la taille de la tumeur ( r = 0,4652, p = 0,0004 pour la rate ; r = 0,2766, p = 0,04 pour les ganglions). Le phenotypage des cellules immunitaires infiltrees dans la tumeur a revele, sous regime hyperlipidique contre regime standard, une augmentation des populations immunosuppressives (MDSC : 278 ± 42 contre 57 ± 17 cellules/mg tumeur, p = 0,02) associee a une modification du ratio lymphocytes T cytotoxiques/T regulateurs (LTc/LTreg : 1,4 ± 0,1 contre 12,8 ± 6,8, p = 0,05). Des alterations similaires sur ce rapport ont ete retrouvees dans les organes lymphoides secondaires (rate et ganglions). A contrario, aucune modification n’a ete observee dans le thymus. Conclusion Dans notre modele, le regime hyperlipidique induit une reduction de l’activite physique spontanee des animaux en lien avec une croissance tumorale acceleree. La migration des cellules immunitaires (lymphocytes T, MDSC, etc.) depuis les organes lymphoides secondaires vers la tumeur s’intensifie. Elle se traduit par une hypertrophie des organes lymphoides et une repolarisation de la reponse immunitaire au niveau systemique et tumoral. Ainsi, le regime hyperlipidique induit un recrutement intratumoral de cellules immunosuppressives favorisant la carcinogenese.

Prostaglandins are derived from arachidonic acid metabolism through cyclooxygenase activities. Among prostaglandins (PGs), prostacyclin (PGI2) and PGE2 are strongly involved in the regulation of homeostasis and main physiologic functions. In addition, the synthesis of these two prostaglandins is significantly increased during inflammation. PGI2 and PGE2 exert their biologic actions by binding to their respective receptors, namely prostacyclin receptor (IP) and prostaglandin E2 receptor (EP) 1-4, which belong to the family of G-protein-coupled receptors. IP and EP1-4 receptors are widely distributed in the body and thus play various physiologic and pathophysiologic roles. In this review, we discuss the recent advances in studies using pharmacological approaches, genetically modified animals, and genome-wide association studies regarding the roles of IP and EP1-4 receptors in the immune, cardiovascular, nervous, gastrointestinal, respiratory, genitourinary, and musculoskeletal systems. In particular, we highlight similarities and differences between human and rodents in terms of the specific roles of IP and EP1-4 receptors and their downstream signaling pathways, functions, and activities for each biologic system. We also highlight the potential novel therapeutic benefit of targeting IP and EP1-4 receptors in several diseases based on the scientific advances, animal models, and human studies. SIGNIFICANCE STATEMENT: In this review, we present an update of the pathophysiologic role of the prostacyclin receptor, prostaglandin E2 receptor (EP) 1, EP2, EP3, and EP4 receptors when activated by the two main prostaglandins, namely prostacyclin and prostaglandin E2, produced during inflammatory conditions in human and rodents. In addition, this comparison of the published results in each tissue and/or pathology should facilitate the choice of the most appropriate model for the future studies.