Crosstalk between Platelets and the Immune System: Old Systems with New Discoveries

Platelets are small anucleate cells circulating in the blood. It has been recognized for more than 100 years that platelet adhesion and aggregation at the site of vascular injury are critical events in hemostasis and thrombosis; however, recent studies demonstrated that, in addition to these classic roles, platelets also have important functions in inflammation and the immune response. Platelets contain many proinflammatory molecules and cytokines (e.g., P-selectin, CD40L, IL-1β, etc.), which support leukocyte trafficking, modulate immunoglobulin class switch, and germinal center formation. Platelets express several functional Toll-like receptors (TLRs), such as TLR-2, TLR-4, and TLR-9, which may potentially link innate immunity with thrombosis. Interestingly, platelets also contain multiple anti-inflammatory molecules and cytokines (e.g., transforming growth factor-β and thrombospondin-1). Emerging evidence also suggests that platelets are involved in lymphatic vessel development by directly interacting with lymphatic endothelial cells through C-type lectin-like receptor 2. Besides the active contributions of platelets to the immune system, platelets are passively targeted in several immune-mediated diseases, such as autoimmune thrombocytopenia, infection-associated thrombocytopenia, and fetal and neonatal alloimmune thrombocytopenia. These data suggest that platelets are important immune cells and may contribute to innate and adaptive immunity under both physiological and pathological conditions

Role of specific cAMP hydrolyzing phosphodiesterase (PDE4) in two chronic inflammatory models,systemic lupus erythematosus and asthma

L'inflammation chronique est un processus délétère qui survient dans de nombreuses pathologies comme les maladies auto-immunes et les affections pulmonaires récurrentes. Elle cause à long terme des dommages tissulaires et la dysfonction des organes concernés. Les phosphodiestérases qui hydrolysent spécifiquement l'AMPc, comme les isoformes de PDE4, sont impliquées dans le contrôle de la réponse inflammatoire. En effet, l'inflammation est fortement corrélée à un bas taux d'AMPc intracellulaire qui résulte d'une augmentation des activités hydrolytiques des PDE Nous avons émis l'hypothèse que certaines maladies inflammatoires chroniques comme le lupus et l'asthme seraient associées à des altérations de voies de signalisations impliquant les phosphodiestérases de type 4 (PDE4). Le but de ce travail est d'étudier le rôle des PDE4 et les conséquences de leur inhibition dans l'inflammation chronique. Pour cela, les activités enzymatiques, les propriétés pharmacomécaniques et biochimiques susceptibles d'être modulées par une élévation de l'AMPc intracellulaire suite à l'inhibition des PDE4 ont été analysées. Dans le modèle lupique murin, nous avons montré que la progression de la maladie est corrélée à une augmentation de l'activité des PDE4. Ce changement d'activité hydrolytique des PDE4s dans le rein chez la souris lupique est associé à des altérations d'expression de certains isoformes de PDE4 (4A, 4B, 4C et 4D). Parmi les 3 inhibiteurs de PDE4 administrés aux souris lupiques MRL/lpr (pentoxifylline, Denbufylline et NSC613), seul le NCS 613 augmente significativement la survie des animaux traités tout en retardant l'apparition des auto-anticorps, la protéinurie et la sécrétion de TNFa. Nous avons également montré que le traitement chronique par le NCS 613 augmente le taux d'AMPc dans le rein des animaux traités, ce qui est fortement corrélé à la baisse d'inflammation dans ce tissu. De plus, ce traitement reverse les altérations d'expressions des PDE4 observées au cours du lupus. Au niveau pulmonaire, nous avons caractérisé une forte activité PDE4 dans le parenchyme humain ainsi que la compartimentation des 4 isoformes de PDE4 dans les fractions cytosoliques, microsomales et nucléaires. Nous avons aussi démontré par des études fonctionnelles que le NCS 613 prévient l'hyperréactivité bronchique résultant de l'inflammation induite in vitro. En outre le NCS 613 diminue les tensions mécaniques induites par les agonistes (méthacholine, histamine et U-46619) dans les bronches humaines traitées au TNFa. Au niveau tissulaire, le NCS 613 diminue l'inflammation en augmentant le taux d'AMPc dans le rein des souris lupiques et en protégeant la dégradation d'I Ba dans les tissus pulmonaires mis en culture. Du point de vue cellulaire et moléculaire, le NCS 613 exerce son effet anti-inflammatoire en inhibant la voie de signalisation de la phospho-p38 MAPK et de NF B dans les cellules mononuclées du sang périphérique de patient lupique et les cellules de lignée A549. Les résultats de ces travaux confirment que les PDE4 sont impliquées dans l'inflammation chronique (du lupus et de l'asthme) et que leur inhibition pourrait constituer une stratégie thérapeutique alternative au corticostéroides. Le NCS 613 est un nouvel inhibiteur de PDE4 qui exerce son effet anti-inflammatoire au niveau systémique, tissulaire et subcellulaire. Son utilisation serait potentiellement bénéfique pour le traitement du lupus et de l'asthme dû au fait que contrairement à d'autres inhibiteurs de PDE4 le NCS 613 a peu d'effet émétique.Chronic inflammation is a deleterious process which occurs in several pathologies such as the autoimmune diseases and the recurrent pulmonary diseases. It causes in the long term tissue damage and the concerned organ dysfunction. The phosphodiesterases which specifically hydrolyze cAMP, like PDE4 isozymes, are believed to be involved in the control of the inflammatory response. Indeed, the inflammation is strongly correlated to low intracellular cAMP level which results from an increase in PDE hydrolytic activities. We hypothesize that chronic inflammatory diseases (such as lupus and asthma) would be associated toPDE4 signaling alterations. The goal of this work is to investigate the role of PDE4 and the consequences of their inhibition in the chronic inflammation. Thus for the enzymatic activities, the pharmaco-mechanical and biochemical properties which are likely modulated by a rise in intracellular cAMP following the inhibition of PDE4 were analyzed. In the murine lupic model, we showed that the disease progression is correlated with an increase in PDE4 activity. This change of PDE4 hydrolytic activity in the MRL/lpr lupus- prone mouse kidney is associated with alterations in PDE4 expression (4A, 4B, 4C and 4D). Among the three PDE4 inhibitors (pentoxifylline, Denbufylline and NSC613) administrated to lupus-prone mice, only the NCS 613 significantly increases the survival of the treated animals while delaying the production of the auto-antibodies, the proteinuria and the secretion of TNFa. We also showed that the chronic treatment with NCS 613 increases the cAMP level in the kidney, which is strongly correlated to a lower inflammation status in this tissue. Moreover, this treatment reversed changes in PDE4 expression level observed during the lupus disease progression. In human lung parenchyma, we have characterized a high PDE4 activity as well as the expression of the four PDE4 isoenzymes in the cytosolic, microsomal and nuclear fractions. Functional studies demonstrated that NCS 613 prevented huaman bronchial hyperresponsiveness resulting from the inflammation induced in vitro. Moreover, the NCS 613 decreases mechanical tensions induced by three independent agonists (methacholine, histamine and U-46619) in TNFa-treated bronchi. NCS 613 also decreases inflammation markers by increasing kidney cAMP level of the lupic mice and by protecting IBa degradation in cultured pulmonary parenchyma. NCS 613 exerts its anti-inflammatory effect by inhibiting phospho-p38 MAPK and NFB pathways in PBMC from lupic patient and A549 cell line. The results of this work confirm that PDE4 are directly involved in chronic inflammations (lupus and asthma) and that their inhibition could constitute an alternative therapeutic strategy to corticosteroids. NCS 613 is a novel PDE4 inhibitor which exerts its anti-inflammatory effect at the systemic, tissue and subcellular levels. Its use would be potentially beneficial for the treatment of the lupus and asthma due to the fact that contrary to other PDE4 inhibitors NCS 613 has basically no emetic effect

Role of specific cAMP hydrolyzing phosphodiesterase (PDE4) in two chronic inflammatory models,systemic lupus erythematosus and asthma

L'inflammation chronique est un processus délétère qui survient dans de nombreuses pathologies comme les maladies auto-immunes et les affections pulmonaires récurrentes. Elle cause à long terme des dommages tissulaires et la dysfonction des organes concerChronic inflammation is a deleterious process which occurs in several pathologies such as the autoimmune diseases and the recurrent pulmonary diseases. It causes in the long term tissue damage and the concerned organ dysfunction. The phosphodiesterases w

Crosstalk between Platelets and the Immune System: Old Systems with New Discoveries

Platelets are small anucleate cells circulating in the blood. It has been recognized for more than 100 years that platelet adhesion and aggregation at the site of vascular injury are critical events in hemostasis and thrombosis; however, recent studies demonstrated that, in addition to these classic roles, platelets also have important functions in inflammation and the immune response. Platelets contain many proinflammatory molecules and cytokines (e.g., P-selectin, CD40L, IL-1β, etc.), which support leukocyte trafficking, modulate immunoglobulin class switch, and germinal center formation. Platelets express several functional Toll-like receptors (TLRs), such as TLR-2, TLR-4, and TLR-9, which may potentially link innate immunity with thrombosis. Interestingly, platelets also contain multiple anti-inflammatory molecules and cytokines (e.g., transforming growth factor-β and thrombospondin-1). Emerging evidence also suggests that platelets are involved in lymphatic vessel development by directly interacting with lymphatic endothelial cells through C-type lectin-like receptor 2. Besides the active contributions of platelets to the immune system, platelets are passively targeted in several immune-mediated diseases, such as autoimmune thrombocytopenia, infection-associated thrombocytopenia, and fetal and neonatal alloimmune thrombocytopenia. These data suggest that platelets are important immune cells and may contribute to innate and adaptive immunity under both physiological and pathological conditions.Peer Reviewe

Fetal and neonatal alloimmune thrombocytopenia.

Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is an alloimmune disorder resulting from platelet opsonization by maternal antibodies that destroy fetal platelets. The major risk of FNAIT is severe bleeding, particularly intracranial hemorrhage. Miscarriage has also been reported but the incidence requires further study. Analogous to adult autoimmune thrombocytopenia (ITP), the major target antigen in FNAIT is the platelet membrane glycoprotein (GP)IIbIIIa. FNAIT caused by antibodies against platelet GPIbα or other antigens has also been reported, but the reported incidence of the anti-GPIbα-mediated FNAIT is far lower than in ITP. To date, the maternal immune response to fetal platelet antigens is still not well understood and it is unclear why bleeding is more severe in FNAIT than in ITP. In this review, we introduce the pathogenesis of FNAIT, particularly those new discoveries from animal models, and discuss possible improvements for the diagnosis, therapy, and prevention of this devastating disease

Treating murine inflammatory diseases with an anti-erythrocyte antibody

Treatment of autoimmune and inflammatory diseases typically involves immune suppression. In an opposite strategy, we show that administration of the highly inflammatory erythrocyte-specific antibody Ter119 into mice remodels the monocyte cellular landscape, leading to resolution of inflammatory disease. Ter119 with intact Fc function was unexpectedly therapeutic in the K/BxN serum transfer model of arthritis. Similarly, it rapidly reversed clinical disease progression in collagen antibody-induced arthritis (CAIA) and collagen-induced arthritis and completely corrected CAIA-induced increase in monocyte Fcγ receptor II/III expression. Ter119 dose-dependently induced plasma chemokines CCL2, CCL5, CXCL9, CXCL10, and CCL11 with corresponding alterations in monocyte percentages in the blood and liver within 24 hours. Ter119 attenuated chemokine production from the synovial fluid and prevented the accumulation of inflammatory cells and complement components in the synovium. Ter119 could also accelerate the resolution of hypothermia and pulmonary edema in an acute lung injury model. We conclude that this inflammatory anti-erythrocyte antibody simultaneously triggers a highly efficient anti-inflammatory effect with broad therapeutic potential