RESUMEN
Mutations in profilin 1 (PFN1) have been identified in rare familial cases of Amyotrophic Lateral Sclerosis (ALS). PFN1 is involved in multiple pathways that could intervene in ALS pathology. However, the specific pathogenic role of PFN1 mutations in ALS is still not fully understood. We hypothesized that PFN1 could play a role in regulating autophagy pathways and that PFN1 mutations could disrupt this function. We used patient cells (lymphoblasts) or tissue (post-mortem) carrying PFN1 mutations (M114T and E117G), and designed experimental models expressing wild-type or mutant PFN1 (cell lines and novel PFN1 mice established by lentiviral transgenesis) to study the effects of PFN1 mutations on autophagic pathway markers. We observed no accumulation of PFN1 in the spinal cord of one E117G mutation carrier. Moreover, in patient lymphoblasts and transfected cell lines, the M114T mutant PFN1 protein was unstable and deregulated the RAB9-mediated alternative autophagy pathway involved in the clearance of damaged mitochondria. In vivo, motor neurons expressing M114T mutant PFN1 showed mitochondrial abnormalities. Our results demonstrate that the M114T PFN1 mutation is more deleterious than the E117G variant in patient cells and experimental models and suggest a role for the RAB9-dependent autophagic pathway in ALS.
Asunto(s)
Esclerosis Amiotrófica Lateral , Profilinas , Proteínas de Unión al GTP rab , Esclerosis Amiotrófica Lateral/metabolismo , Animales , Autofagia/genética , Homeostasis , Humanos , Ratones , Mitocondrias/metabolismo , Mutación , Profilinas/genética , Profilinas/metabolismo , Proteínas de Unión al GTP rab/metabolismoRESUMEN
OBJECTIVE: The lymphatic system is a circulatory system that unidirectionally drains the interstitial tissue fluid back to blood circulation. Although lymph is utilized by leukocytes for immune surveillance, it remains inaccessible to platelets and erythrocytes. Activated cells release submicron extracellular vesicles (EV) that transport molecules from the donor cell. In rheumatoid arthritis, EV accumulate in the joint where they can interact with numerous cellular lineages. However, whether EV can exit the inflamed tissue to recirculate is unknown. Here, we investigated whether vascular leakage that occurs during inflammation could favor EV access to the lymphatic system. Approach and Results: Using an in vivo model of autoimmune inflammatory arthritis, we show that there is an influx of platelet EV, but not EV from erythrocytes or leukocytes, in joint-draining lymph. In contrast to blood platelet EV, lymph platelet EV lacked mitochondrial organelles and failed to promote coagulation. Platelet EV influx in lymph was consistent with joint vascular leakage and implicated the fibrinogen receptor α2bß3 and platelet-derived serotonin. CONCLUSIONS: These findings show that platelets can disseminate their EV in fluid that is inaccessible to platelets and beyond the joint in this disease.
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Artritis Reumatoide/fisiopatología , Plaquetas/fisiología , Vesículas Extracelulares/fisiología , Linfa/fisiología , Animales , Plaquetas/metabolismo , Permeabilidad Capilar , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Serotonina/metabolismoRESUMEN
There is a growing appreciation for the contribution of platelets to immunity; however, our knowledge mostly relies on platelet functions associated with vascular injury and the prevention of bleeding. Circulating immune complexes (ICs) contribute to both chronic and acute inflammation in a multitude of clinical conditions. Herein, we scrutinized platelet responses to systemic ICs in the absence of tissue and endothelial wall injury. Platelet activation by circulating ICs through a mechanism requiring expression of platelet Fcγ receptor IIA resulted in the induction of systemic shock. IC-driven shock was dependent on release of serotonin from platelet-dense granules secondary to platelet outside-in signaling by αIIbß3 and its ligand fibrinogen. While activated platelets sequestered in the lungs and leaky vasculature of the blood-brain barrier, platelets also sequestered in the absence of shock in mice lacking peripheral serotonin. Unexpectedly, platelets returned to the blood circulation with emptied granules and were thereby ineffective at promoting subsequent systemic shock, although they still underwent sequestration. We propose that in response to circulating ICs, platelets are a crucial mediator of the inflammatory response highly relevant to sepsis, viremia, and anaphylaxis. In addition, platelets recirculate after degranulation and sequestration, demonstrating that in adaptive immunity implicating antibody responses, activated platelets are longer lived than anticipated and may explain platelet count fluctuations in IC-driven diseases.
Asunto(s)
Anafilaxia/inmunología , Complejo Antígeno-Anticuerpo/inmunología , Plaquetas/inmunología , Serotonina/inmunología , Choque Séptico/inmunología , Adulto , Anafilaxia/sangre , Anafilaxia/genética , Animales , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Activación Plaquetaria , Recuento de Plaquetas , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria/genética , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria/inmunología , Receptores de IgG/genética , Receptores de IgG/inmunología , Choque Séptico/sangre , Choque Séptico/genética , Adulto JovenRESUMEN
Anemia is known to be associated with depression both in community and clinical populations. However, it is still unknown if this association depends or not on antidepressant intake. We investigated the respective association of depression and antidepressant intake with low hemoglobin level in a large community-based cohort. In 8640 volunteers aged 50 to 75 recruited between June 2008 and June 2012 in Paris (France), we assessed hemoglobin levels (g/dl), depressive symptoms and antidepressant intake. We examined the association of both depression and antidepressant intake with hemoglobin level, adjusting for numerous socio-demographic and health variables. We also assessed the association with specific antidepressant classes. Depression and antidepressant intake were independently associated with lower hemoglobin level (ß = -0.074; p = .05 and ß = -0.100; p = .02 respectively in the fully-adjusted model). Regarding antidepressant classes, selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) intake were associated with lower hemoglobin level (ß = -0.11; p = .01). To conclude, both depression and antidepressant intake were associated with lower hemoglobin level. In particular, as SSRI or SNRIs intake was also related to lower hemoglobin level, these classes should be used with caution in depressed individuals at risk for anemia.
Asunto(s)
Antidepresivos/uso terapéutico , Depresión/tratamiento farmacológico , Hemoglobinas/deficiencia , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico , Anciano , Anemia/complicaciones , Antidepresivos/clasificación , Estudios Transversales , Femenino , Francia , Humanos , Masculino , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
A large number of studies have focused on the role of serotonin as a neurotransmitter in the central nervous system, although only a small percentage of the body's serotonin (â¼5%) can be found in the mature brain of mammals. In the gut, the enterochromaffin cells are scattered in the enteric epithelium from the stomach through the colon and produce over 95% of the body's serotonin. Since the generation of tryptophan hydroxylase (Tph1 and Tph2) knockout mice, unsuspected roles have been identified for serotonin synthesized outside the brain. Moreover, the murine model deficient in peripheral serotonin (Tph1-/-) is a unique experimental tool for exploring the molecular and cellular mechanisms involving serotonin's local effects through microserotonergic systems. In this review, we focus on peripheral serotonin and its role on progenitor or stem cells as well as on hematopoietic progenitors. We discuss the possible role of serotonin in hematopoietic diseases, and whether targeting the serotonergic system could be of therapeutic value for the regulation of normal and pathological hematopoiesis.
Asunto(s)
Hematopoyesis , Serotonina/fisiología , Células Madre/fisiología , Animales , Desarrollo Embrionario , Humanos , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéuticoRESUMEN
Serotonin (5-hydroxytryptamine, 5-HT) is a well-known neurotransmitter that is involved in a growing number of functions in peripheral tissues. Recent studies have shown nonpharmacological functions of 5-HT linked to its chemical properties. Indeed, it was reported that 5-HT may, on the one hand, bind lipid membranes and, on the other hand, protect red blood cells through a mechanism independent of its specific receptors. To better understand these underevaluated properties of 5-HT, we combined biochemical, biophysical, and molecular dynamics simulations approaches to characterize, at the molecular level, the antioxidant capacity of 5-HT and its interaction with lipid membranes. To do so, 5-HT was added to red blood cells and lipid membranes bearing different degrees of unsaturation. Our results demonstrate that 5-HT acts as a potent antioxidant and binds with a superior affinity to lipids with unsaturation on both alkyl chains. We show that 5-HT locates at the hydrophobic-hydrophilic interface, below the glycerol group. This interfacial location is stabilized by hydrogen bonds between the 5-HT hydroxyl group and lipid headgroups and allows 5-HT to intercept reactive oxygen species, preventing membrane oxidation. Experimental and molecular dynamics simulations using membrane enriched with oxidized lipids converge to further reveal that 5-HT contributes to the termination of lipid peroxidation by direct interaction with active groups of these lipids and could also contribute to limit the production of new radicals. Taken together, our results identify 5-HT as a potent inhibitor of lipid peroxidation and offer a different perspective on the role of this pleiotropic molecule.
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Antioxidantes/metabolismo , Membrana Celular/metabolismo , Lípidos de la Membrana/metabolismo , Serotonina/metabolismo , Antioxidantes/administración & dosificación , Antioxidantes/química , Membrana Celular/química , Eritrocitos/química , Eritrocitos/metabolismo , Citometría de Flujo , Humanos , Enlace de Hidrógeno , Interacciones Hidrofóbicas e Hidrofílicas , Membrana Dobles de Lípidos/química , Membrana Dobles de Lípidos/metabolismo , Peroxidación de Lípido , Liposomas/química , Liposomas/metabolismo , Microscopía Confocal , Simulación de Dinámica Molecular , Oxidación-Reducción , Serotonina/administración & dosificación , Serotonina/químicaRESUMEN
Rheumatoid arthritis is a chronic disease that results in a disabling and painful condition as it progresses to destruction of the articular cartilage and ankylosis of the joints. Although the cause of the disease is still unknown, evidence argues that autoimmunity plays an important part. There are increasing but contradictory views regarding serotonin being associated with activation of immunoinflammatory pathways and the onset of autoimmune reactions. We studied serotonin's involvement during collagen-induced arthritis in wild-type and Tph1(-/-) mice, which have markedly reduced peripheral serotonin levels. In wild-type mice, induction of arthritis triggered a robust increase in serotonin content in the paws combined with less inflammation. In Tph1(-/-) mice with arthritis, a marked increase in the clinical and pathologic arthritis scores was noticed. Specifically, in Tph1(-/-) mice with arthritis, a significant increase in osteoclast differentiation and bone resorption was observed with an increase in IL-17 levels in the paws and in Th17 lymphocytes in the draining lymph nodes, whereas T-regulatory cells were dampened. Ex vivo serotonin and agonists of the 5-HT2A and 5-HT2B receptors restored IL-17 secretion from splenocytes and Th17 cell differentiation in Tph1(-/-) mice. These findings indicate that serotonin plays a fundamental role in arthritis through the regulation of the Th17/T-regulatory cell balance and osteoclastogenesis.
Asunto(s)
Artritis Experimental/patología , Enfermedades Autoinmunes/inmunología , Resorción Ósea/patología , Serotonina/metabolismo , Linfocitos T Reguladores/inmunología , Células Th17/inmunología , Animales , Artritis Experimental/inmunología , Enfermedades Autoinmunes/patología , Resorción Ósea/inmunología , Diferenciación Celular , Modelos Animales de Enfermedad , Ratones Noqueados , Serotonina/inmunologíaRESUMEN
Peripheral serotonin, synthesized by tryptophan hydroxylase-1 (TPH(1)), has been shown to play a key role in several physiological functions. Recently, controversy has emerged about whether peripheral serotonin has any effect on bone density and remodeling.We therefore decided to investigate in detail bone remodeling in growing and mature TPH(1) knockout mice (TPH(1)(-/-)). Bone resorption in TPH(1)(-/-) mice, as assessed by biochemical markers and bone histomorphometry, was markedly decreased at both ages. Using bone marrow transplantation, we present evidence that the decrease in bone resorption in TPH(1)(-/-) mice is cell-autonomous. Cultures from TPH(1)(-/-) in the presence of macrophage colony-stimulating factor and receptor activator for NF-KB ligand (RANKL) displayed fewer osteoclasts, and the decreased differentiation could be rescued by adding serotonin. Our data also provide evidence that in the presence of RANKL, osteoclast precursors express TPH(1) and synthesize serotonin. Furthermore, pharmacological inhibition of serotonin receptor 1B with SB224289, and of receptor 2A with ketanserin, also reduced the number of osteoclasts. Our findings reveal that serotonin has an important local action in bone, as it can amplify the effect of RANKL on osteoclastogenesis.
Asunto(s)
Osteoclastos/citología , Serotonina/genética , Triptófano Hidroxilasa/genética , Animales , Diferenciación Celular , Ratones , Ratones NoqueadosRESUMEN
Pulmonary arterial hypertension (PAH) is a progressive disease characterized by lung endothelial dysfunction and vascular remodeling. Recently, bone marrow progenitor cells have been localized to PAH lungs, raising the question of their role in disease progression. Independently, serotonin (5-HT) and its receptors have been identified as contributors to the PAH pathogenesis. We hypothesized that 1 of these receptors, 5-HT(2B), is involved in bone marrow stem cell mobilization that participates in the development of PAH and pulmonary vascular remodeling. A first study revealed expression of 5-HT(2B) receptors by circulating c-kit(+) precursor cells, whereas mice lacking 5-HT(2B) receptors showed alterations in platelets and monocyte-macrophage numbers, and in myeloid lineages of bone marrow. Strikingly, mice with restricted expression of 5-HT(2B) receptors in bone marrow cells developed hypoxia or monocrotaline-induced increase in pulmonary pressure and vascular remodeling, whereas restricted elimination of 5-HT(2B) receptors on bone marrow cells confers a complete resistance. Moreover, ex vivo culture of human CD34(+) or mice c-kit(+) progenitor cells in the presence of a 5-HT(2B) receptor antagonist resulted in altered myeloid differentiation potential. Thus, we demonstrate that activation of 5-HT(2B) receptors on bone marrow lineage progenitors is critical for the development of PAH.
Asunto(s)
Médula Ósea/fisiología , Hipertensión Pulmonar/genética , Receptor de Serotonina 5-HT2B/fisiología , Animales , Sangre/metabolismo , Análisis Químico de la Sangre , Médula Ósea/metabolismo , Células de la Médula Ósea/metabolismo , Células de la Médula Ósea/fisiología , Diferenciación Celular/genética , Células Cultivadas , Hipertensión Pulmonar Primaria Familiar , Femenino , Humanos , Hipertensión Pulmonar/sangre , Hipertensión Pulmonar/inmunología , Hipertensión Pulmonar/metabolismo , Pulmón/metabolismo , Masculino , Ratones , Ratones Noqueados , Modelos Biológicos , Proteínas Proto-Oncogénicas c-kit/genética , Proteínas Proto-Oncogénicas c-kit/metabolismo , Receptor de Serotonina 5-HT2B/genética , Receptor de Serotonina 5-HT2B/metabolismoRESUMEN
Serotonin (5-HT) has long been recognized as a neurotransmitter in the central nervous system, where it modulates a variety of behavioral functions. Availability of 5-HT depends on the expression of the enzyme tryptophan hydroxylase (TPH), and the recent discovery of a dual system for 5-HT synthesis in the brain (TPH2) and periphery (TPH1) has renewed interest in studying the potential functions played by 5-HT in nonnervous tissues. Moreover, characterization of the TPH1 knockout mouse model (TPH1(-/-)) led to the identification of unsuspected roles for peripheral 5-HT, revealing the importance of this monoamine in regulating key physiological functions outside the brain. Here, we present in vivo data showing that mice deficient in peripheral 5-HT display morphological and cellular features of ineffective erythropoiesis. The central event occurs in the bone marrow where the absence of 5-HT hampers progression of erythroid precursors expressing 5-HT(2A) and 5-HT(2B) receptors toward terminal differentiation. In addition, red blood cells from 5-HT-deficient mice are more sensitive to macrophage phagocytosis and have a shortened in vivo half-life. The combination of these two defects causes TPH1(-/-) animals to develop a phenotype of macrocytic anemia. Direct evidence for a 5-HT effect on erythroid precursors is provided by supplementation of the culture medium with 5-HT that increases the proliferative capacity of both 5-HT-deficient and normal cells. Our thorough analysis of TPH1(-/-) mice provides a unique model of morphological and functional aberrations of erythropoiesis and identifies 5-HT as a key factor for red blood cell production and survival.
Asunto(s)
Eritrocitos/patología , Eritropoyesis , Serotonina/deficiencia , Anemia Macrocítica/complicaciones , Anemia Macrocítica/enzimología , Anemia Macrocítica/patología , Animales , Médula Ósea/efectos de los fármacos , Médula Ósea/patología , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Suplementos Dietéticos , Eritrocitos/efectos de los fármacos , Eritrocitos/enzimología , Células Precursoras Eritroides/metabolismo , Células Precursoras Eritroides/patología , Eritropoyesis/efectos de los fármacos , Hierro/metabolismo , Ratones , Ratones Endogámicos C57BL , Fenotipo , Receptores de Serotonina/metabolismo , Serotonina/farmacología , Agonistas de Receptores de Serotonina/farmacología , Siderosis/complicaciones , Siderosis/patología , Bazo/efectos de los fármacos , Bazo/patología , Triptófano Hidroxilasa/deficiencia , Triptófano Hidroxilasa/metabolismoRESUMEN
INTRODUCTION: Microcytic anemias (MA) have frequent or rare etiologies. New discoveries in understanding and treatment of microcytic anemias need to be reviewed. AREAS COVERED: Microcytic anemias with a focus on the most frequent causes and on monogenic diseases that are relevant for understanding biocellular mechanisms of MA. All treatments except gene therapy, with a focus on recent advances. PubMed search with references selected by expert opinion. EXPERT OPINION: As the genetic and cellular backgrounds of dyserythropoiesis will continue to be clarified, collaboration with bioengineering of treatments acting specifically at the protein domain level will continue to provide new therapies in hematology as well as oncology and neurology.
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Anemia Hipocrómica , Humanos , Anemia Hipocrómica/genética , Anemia Hipocrómica/metabolismo , Testimonio de Experto , Terapia GenéticaRESUMEN
The gut contains a large 5-HT pool in enterochromaffin (EC) cells and a smaller 5-HT pool in the enteric nervous system (ENS). During development, enteric neurons are generated asynchronously. We tested hypotheses that serotonergic neurons, which arise early, affect development/survival of later-born dopaminergic, GABAergic, nitrergic, and calcitonin gene-related peptide-expressing neurons and are essential for gastrointestinal motility. 5-HT biosynthesis depends on tryptophan hydroxylase 1 (TPH1) in EC cells and on TPH2 in neurons; therefore, mice lacking TPH1 and/or TPH2 distinguish EC-derived from neuronal 5-HT. Deletion of TPH2, but not TPH1, decreased myenteric neuronal density and proportions of dopaminergic and GABAergic neurons but did not affect the extrinsic sympathetic innervation of the gut; intestinal transit slowed in mice lacking TPH2 mice, but gastric emptying accelerated. Isolated enteric crest-derived cells (ENCDCs) expressed the serotonin reuptake transporter (SERT) and 15 subtypes of 5-HT receptor. Addition of 5-HT to cultures of isolated ENCDCs promoted total and dopaminergic neuronal development. Rings of SERT-immunoreactive terminal axons surrounded myenteric dopaminergic neurons and SERT knock-out increased intestinal levels of dopamine metabolites, implying that enteric dopaminergic neurons receive a serotonergic innervation. Observations suggest that constitutive gastrointestinal motility depends more on neuronal than EC cell serotonin; moreover, serotonergic neurons promote development/survival of some classes of late-born enteric neurons, including dopaminergic neurons, which appear to innervate and activate in the adult ENS.
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Dopamina/metabolismo , Sistema Nervioso Entérico/citología , Motilidad Gastrointestinal/fisiología , Regulación del Desarrollo de la Expresión Génica/fisiología , Neuronas/metabolismo , Serotonina/metabolismo , Animales , Péptido Relacionado con Gen de Calcitonina/metabolismo , Proteínas ELAV/metabolismo , Proteína 3 Similar a ELAV , Embrión de Mamíferos , Inhibidores Enzimáticos/farmacología , Vaciamiento Gástrico/efectos de los fármacos , Vaciamiento Gástrico/genética , Motilidad Gastrointestinal/efectos de los fármacos , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Regulación del Desarrollo de la Expresión Génica/genética , Ácido Homovanílico/análogos & derivados , Ácido Homovanílico/metabolismo , Técnicas In Vitro , Intestino Delgado/fisiología , Ratones , Ratones Endogámicos C57BL , Plexo Mientérico/efectos de los fármacos , Plexo Mientérico/metabolismo , Neuronas/efectos de los fármacos , Óxido Nítrico Sintasa de Tipo I/metabolismo , Serotonina/farmacología , Proteínas de Transporte de Serotonina en la Membrana Plasmática/deficiencia , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Triptófano Hidroxilasa/deficiencia , Tirosina 3-Monooxigenasa/metabolismo , Ácido gamma-Aminobutírico/metabolismoRESUMEN
Mucosal inflammation in the gut is characterized by infiltration of innate and adaptive immune cells and by an alteration in serotonin-producing enterochromaffin cells. We investigated the role of serotonin in the function of dendritic cells (DCs) and sequential T-cell activation in relation to generation of gut inflammation. DCs isolated from tryptophan hydroxylase-1-deficient (TPH1(-/-)) mice, which have reduced serotonin in the gut, and wild-type (TPH1(+/+)) mice with or without dextran sulfate sodium (DSS)-induced colitis were stimulated with lipopolysaccharide to assess interleukin-12 (IL-12) production. Isolated DCs from TPH1(+/+) and TPH1(-/-) mice were also cocultured with CD4(+) T cells of naive TPH1(+/+) mice to assess the role of serotonin in priming T cells. In addition, serotonin-pulsed DCs were transferred to TPH1(-/-) mice to assess the effect on DSS-induced colitis. Consistent with a reduced severity of colitis, DCs from DSS-induced TPH1(-/-) mice produced less IL-12 compared with the TPH1(+/+) mice. In vitro serotonin stimulation restored the cytokine production from TPH1(-/-) DCs and adoptive transfer of serotonin-pulsed DCs into TPH1(-/-) up-regulated colitis. Furthermore, CD4(+) T cells primed by TPH1(-/-) DCs produce reduced the levels of IL-17 and interferon-γ. This study provides novel information on serotonin-mediated immune signaling and promotion of interactions between innate and adaptive immune responses in the context of gut inflammation, which may ultimately lead to improved strategies to combat gut inflammatory disorders.
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Células Dendríticas/metabolismo , Sistema Digestivo/patología , Inflamación/patología , Serotonina/metabolismo , Traslado Adoptivo , Animales , Biomarcadores/metabolismo , Células de la Médula Ósea/metabolismo , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Separación Celular , Colitis/inducido químicamente , Colitis/patología , Reactividad Cruzada/efectos de los fármacos , Citocinas/biosíntesis , Células Dendríticas/efectos de los fármacos , Sulfato de Dextran , Sistema Digestivo/efectos de los fármacos , Sistema Digestivo/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Inflamación/metabolismo , Ratones , Ratones Endogámicos C57BL , Serotonina/farmacologíaRESUMEN
BACKGROUND: Murine basophils can contribute to the T(H)2 polarization of the immune response by providing rapidly large amounts of IL-4, which suggests that pharmacologic downregulation of this cytokine might provide a strategy to attenuate pathologies associated with excessive production. OBJECTIVE: We examined a number of physiological and pharmacologic ligands of the organic cation transporter 3 (OCT3), a membrane carrier of biogenic amines, for their inhibitory effect on IL-4 production by basophils, selecting the most efficient compounds for in vivo evaluation in basophil-dependent experimental models. METHODS: IL-4 production by basophils isolated ex vivo or from bone marrow cultures was assessed in response to various stimuli with or without biogenic monoamines or pharmacologic analogs. Selected compounds were administered in vivo to examine their effect on levels of circulating IgE generated during a basophil-dependent T(H)2 response and on basophil activation in mice receiving IL-33. RESULTS: We found a drastic decrease in IL-4 production by stimulated basophils on exposure to serotonin (5-hydroxytryptamine [5-HT]) that is taken up by basophils through the specific high-affinity transporters serotonin transporter and the polyspecific, high-capacity organic cation transporter 3 (OCT3; or Slc22a3) but inhibits their function exclusively through the latter. This downregulation is likewise observed in vivo in response to 5-HT and other OCT3 ligands, as well as in human basophils sorted from PMBCs of nonatopic donors. CONCLUSIONS: We provide evidence for a new means of downregulating IL-4 production by basophils, both in vitro and in vivo, through OCT3 targeted by 5-HT and pharmacologic ligands.
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Basófilos/inmunología , Inmunoglobulina E/inmunología , Interleucina-4/inmunología , Proteínas de Transporte de Catión Orgánico/agonistas , Serotonina/inmunología , Células Th2/inmunología , Animales , Basófilos/metabolismo , Células de la Médula Ósea/inmunología , Células de la Médula Ósea/metabolismo , Células Cultivadas , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/genética , Regulación hacia Abajo/inmunología , Femenino , Humanos , Inmunoglobulina E/metabolismo , Interleucina-33 , Interleucina-4/biosíntesis , Interleucina-4/genética , Interleucinas/inmunología , Interleucinas/farmacología , Ligandos , Masculino , Ratones , Ratones Noqueados , Proteínas de Transporte de Catión Orgánico/genética , Proteínas de Transporte de Catión Orgánico/inmunología , Proteínas de Transporte de Catión Orgánico/metabolismo , Serotonina/genética , Serotonina/metabolismo , Serotonina/farmacología , Agonistas de Receptores de Serotonina/inmunología , Agonistas de Receptores de Serotonina/metabolismo , Agonistas de Receptores de Serotonina/farmacología , Células Th2/metabolismoRESUMEN
The hematopoietic system uses several, yet undiscovered, factors to adapt to stresses such as chemotherapy, infections, or bleeding. Serotonin is commonly known as a neurotransmitter but is also produced and used in peripheral organs. In particular, we have shown that serotonin synthesized in the bone marrow is necessary for erythroid progenitors' survival and proliferation. Serotonin levels can be increased by FDA approved antidepressants called selective serotonin reuptake inhibitors (SSRI). In this work, we report a previously unknown role of SSRI in the recovery of cytopenia, after autologous hematopoietic stem cell transplantation in patients and after sub-lethal irradiation in mice. We also observed an unexpected cooperation between SSRI and G-CSF on the improvement of the 3 hematopoietic lineages. Of note, SSRI do not seem to affect blood cells production in the absence of stress-induced hematopoiesis. We propose that the serotonergic system could be a valuable therapeutic target in stress-induced cytopenia, especially as a rescue after radiation or chemotherapy.
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Inhibidores Selectivos de la Recaptación de Serotonina , Serotonina , Animales , Antidepresivos/farmacología , Factor Estimulante de Colonias de Granulocitos/farmacología , Hematopoyesis , Humanos , Ratones , Serotonina/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéuticoRESUMEN
Targeting immune checkpoints, such as Programmed cell Death 1 (PD1), has improved survival in cancer patients by restoring antitumor immune responses. Most patients, however, relapse or are refractory to immune checkpoint blocking therapies. Neuropilin-1 (NRP1) is a transmembrane glycoprotein required for nervous system and angiogenesis embryonic development, also expressed in immune cells. We hypothesized that NRP1 could be an immune checkpoint co-receptor modulating CD8+ T cells activity in the context of the antitumor immune response. Here, we show that NRP1 is recruited in the cytolytic synapse of PD1+CD8+ T cells, cooperates and enhances PD-1 activity. In mice, CD8+ T cells specific deletion of Nrp1 improves anti-PD1 antibody antitumor immune responses. Likewise, in human metastatic melanoma, the expression of NRP1 in tumor infiltrating CD8+ T cells predicts poor outcome of patients treated with anti-PD1. NRP1 is a promising target to overcome resistance to anti-PD1 therapies.
RESUMEN
Normal fetal development is dependent upon an intricate exchange between mother and embryo. Several maternal and embryonic elements can influence this intimate interaction, including genetic, environmental or epigenetic factors, and have a significant impact on embryo development. The interaction of the genetic program of both mother and embryo, within the uterine environment, can shape the development of an individual. Accumulating data from animal models indicate that prenatal events may well initiate long-term changes in the expression of the embryo genetic program, which persist, or may only become apparent, much later in the individual's life. Also, environmental conditions during prenatal development may prompt the adoption of different developmental pathways, leading to alternative life histories. This review focuses on environmental factors, specifically maternally derived molecules, to illustrate how they can influence in utero embryonic development and, by extension, adult life.
Asunto(s)
Desarrollo Fetal , Mamíferos/metabolismo , Animales , Humanos , Mamíferos/embriología , Madres , Serotonina/metabolismo , Transducción de SeñalRESUMEN
Low levels of the neurotransmitter serotonin have been associated with the onset of depression. While traditional treatments include antidepressants, physical exercise has emerged as an alternative for patients with depressive disorders. Yet there remains the fundamental question of how exercise is sensed by the brain. The existence of a muscle-brain endocrine loop has been proposed: according to this scenario, exercise modulates metabolization of tryptophan into kynurenine within skeletal muscle, which in turn affects the brain, enhancing resistance to depression. But the breakdown of tryptophan into kynurenine during exercise may also alter serotonin synthesis and help limit depression. In this study, we investigated whether peripheral serotonin might play a role in muscle-brain communication permitting adaptation for endurance training. We first quantified tryptophan metabolites in the blood of 4 trained athletes before and after a long-distance trail race and correlated changes in tryptophan metabolism with physical performance. In parallel, to assess exercise capacity and endurance in trained control and peripheral serotonin-deficient mice, we used a treadmill incremental test. Peripheral serotonin-deficient mice exhibited a significant drop in physical performance despite endurance training. Brain levels of tryptophan metabolites were similar in wild-type and peripheral serotonin-deficient animals, and no products of muscle-induced tryptophan metabolism were found in the plasma or brains of peripheral serotonin-deficient mice. But mass spectrometric analyses revealed a significant decrease in levels of 5-hydroxyindoleacetic acid (5-HIAA), the main serotonin metabolite, in both the soleus and plantaris muscles, demonstrating that metabolization of tryptophan into serotonin in muscles is essential for adaptation to endurance training. In light of these findings, the breakdown of tryptophan into peripheral but not brain serotonin appears to be the rate-limiting step for muscle adaptation to endurance training. The data suggest that there is a peripheral mechanism responsible for the positive effects of exercise, and that muscles are secretory organs with autocrine-paracrine roles in which serotonin has a local effect.
RESUMEN
Autophagy, an essential intracellular recycling process, is linked to the pathogenesis of various diseases including Crohn's disease (CD). Factors that lead to the development of impaired autophagy during intestinal inflammation remain largely unexplored. Here, we report the impact of the interaction between serotonin [5-hydroxytryptamine;(5-HT)] and autophagy in colitis in mouse and human studies. In mice, increased gut 5-HT inhibited autophagy and led to enhanced colitis susceptibility. Reciprocally, mice with reduced 5-HT exhibited up-regulated autophagy via the mammalian target of rapamycin pathway, which resulted in significantly decreased colitis. Deletion of autophagy gene, Atg7, in an epithelial-specific manner, in concert with reduced 5-HT, promoted the development of a colitogenic microbiota and abolished the protective effects conferred by reduced 5-HT. Notably, in control and patient peripheral blood mononuclear cells, we uncovered that 5-HT treatment inhibited autophagy. Our findings suggest 5-HT as a previously unidentified therapeutic target in intestinal inflammatory disorders such as CD that exhibits dysregulated autophagy.
RESUMEN
BACKGROUND & AIMS: Mucosal changes in inflammatory bowel disease are characterized by ulcerative lesions accompanied by a prominent infiltrate of immune cells as well as alteration in serotonin (5-hydroxytryptamine [5-HT])-producing enterochromaffin cells. We investigated the role of 5-HT in colonic inflammation in mice. METHODS: Colitis was induced with dextran sulfate sodium or dinitrobenzene sulfonic acid in tryptophan hydroxylase 1-deficient (TPH1(-/-)) mice, which have markedly reduced 5-HT in the gastrointestinal tract, and in mice given the 5-HT synthesis inhibitor parachlorophenylalanine. RESULTS: Delayed onset, decreased severity of clinical disease, and significantly lower macroscopic and histologic damage scores were observed in TPH1(-/-) mice, compared with wild-type mice, and in mice given parachlorophenylalanine after induction of colitis by dextran sulfate sodium. This was associated with down-regulation of macrophage infiltration and production of proinflammatory cytokines. 5-HT stimulated production of proinflammatory cytokines from macrophages collected from the peritoneal cavity of wild-type mice; this process was inhibited by a nuclear factor kappaB inhibitor, indicating a critical role for nuclear factor kappaB signaling in 5-HT-mediated activation of immune cells. Restoration of 5-HT levels in TPH1(-/-) mice by the 5-HT precursor 5-hydroxytryptophan increased the severity of DSS-induced colitis. We also observed significant reduction in severity of colitis in TPH1(-/-) mice after induction of dinitrobenzene sulfonic acid-induced colitis. CONCLUSIONS: 5-HT is involved in the pathogenesis of inflammation in experimental colitis. These findings provide insight into the mechanisms of gastrointestinal inflammation and could lead to new therapeutic strategies for inflammatory disorders.