RESUMEN
Endocannabinoids are key bioactive components of the endocannabinoid system, and the profound influence of endocannabinoids on the modulation of the immune system is being increasingly appreciated. The knowledge of endocannabinoid-immune cell crosstalk will pave the way to therapeutic implications of modulators of this pathway in autoimmune and chronic inflammatory disorders. Endocannabinoids seem to exert both anti-inflammatory and pro-inflammatory effects in specific contexts, based on specific receptor engagement and the downstream signalling pathways involved. In this review, we summarized the biosynthesis, signalling and degradation of two well-studied endocannabinoids-anandamide and 2-arachidonylglycerol in immune cells. Then, we discussed the effects of these two endocannabinoids on the functioning of major innate and adaptive immune cells, along with the choice of receptors employed in such interactions. Finally, we outline our current knowledge on the involvement of anandamide and 2-arachidonylglycerol in context of inflammation, allergies, autoimmunity and metabolic disorders.
Asunto(s)
Inmunidad Adaptativa/inmunología , Endocannabinoides/inmunología , Inmunidad Innata/inmunología , Animales , Ácidos Araquidónicos/inmunología , Glicéridos/inmunología , Humanos , Inflamación/inmunología , Alcamidas Poliinsaturadas/inmunología , Transducción de Señal/inmunologíaRESUMEN
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease, characterized by loss of tolerance toward self nuclear Ags. Systemic induction of type I IFNs plays a pivotal role in SLE, a major source of type I IFNs being the plasmacytoid dendritic cells (pDCs). Several genes have been linked with susceptibility to SLE in genome-wide association studies. We aimed at exploring the role of one such gene, α/ß-hydrolase domain-containing 6 (ABHD6), in regulation of IFN-α induction in SLE patients. We discovered a regulatory role of ABHD6 in human pDCs through modulating the local abundance of its substrate, the endocannabinoid 2-arachidonyl glycerol (2-AG), and elucidated a hitherto unknown cannabinoid receptor 2 (CB2)-mediated regulatory role of 2-AG on IFN-α induction by pDCs. We also identified an ABHD6High SLE endophenotype wherein reduced local abundance of 2-AG relieves the CB2-mediated steady-state resistive tuning on IFN-α induction by pDCs, thereby contributing to SLE pathogenesis.
Asunto(s)
Células Dendríticas/inmunología , Endocannabinoides/metabolismo , Interferón gamma/biosíntesis , Lupus Eritematoso Sistémico/inmunología , Monoacilglicerol Lipasas/inmunología , Adulto , Ácidos Araquidónicos/inmunología , Ácidos Araquidónicos/metabolismo , Células Dendríticas/metabolismo , Endocannabinoides/inmunología , Endofenotipos , Femenino , Regulación de la Expresión Génica/inmunología , Glicéridos/inmunología , Glicéridos/metabolismo , Humanos , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/metabolismo , Masculino , Persona de Mediana Edad , Monoacilglicerol Lipasas/genética , Receptor Cannabinoide CB2/inmunología , Receptor Cannabinoide CB2/metabolismoRESUMEN
Asthma and allergic diseases are inflammatory conditions developed by excessive reaction of the immune system against normally harmless environmental substances. Although acute inflammation is necessary to eradicate the damaging agents, shifting to chronic inflammation can be potentially detrimental. Essential fatty-acids-derived immunoresolvents, namely, lipoxins, resolvins, protectins, and maresins, are anti-inflammatory compounds that are believed to have protective and beneficial effects in inflammatory disorders, including asthma and allergies. Accordingly, impaired biosynthesis and defective production of immunoresolvents could be involved in the development of chronic inflammation. In this review, recent evidence on the anti-inflam]matory effects of immunoresolvents, their enzymatic biosynthesis routes, as well as their receptors are discussed.
Asunto(s)
Asma/metabolismo , Ácidos Grasos Esenciales/metabolismo , Hipersensibilidad/metabolismo , Inflamación/metabolismo , Lipoxinas/metabolismo , Animales , Ácidos Araquidónicos/inmunología , Ácidos Araquidónicos/metabolismo , Asma/inmunología , Asma/fisiopatología , Ácidos Docosahexaenoicos/inmunología , Ácidos Docosahexaenoicos/metabolismo , Ácido Eicosapentaenoico/inmunología , Ácido Eicosapentaenoico/metabolismo , Ácidos Grasos Esenciales/inmunología , Humanos , Hipersensibilidad/inmunología , Hipersensibilidad/fisiopatología , Inflamación/inmunología , Inflamación/fisiopatología , Lipoxinas/inmunología , Receptores de Lipoxina/metabolismo , Transducción de SeñalRESUMEN
Macrophages in adipose tissue are associated with obesity-induced low-grade inflammation, which contributed to insulin resistance and the related metabolic diseases. Macrophages display phenotypic plasticity, and polarize under the condition of obesity. Epoxyeicosatrienoic Acids (EETs) are lipid mediators that are involved in the regulation of inflammatory cascades and glucose homeostasis. In this mini-review, we briefly summarize the macrophages recruitment, infiltration and polarization in obese mice, and also discuss the immune-metabolic regulatory role of EETs in this process (See Fig. 1).
Asunto(s)
Ácidos Araquidónicos/inmunología , Inflamación/inmunología , Resistencia a la Insulina/inmunología , Obesidad/inmunología , Adaptación Fisiológica , Tejido Adiposo/inmunología , Tejido Adiposo/metabolismo , Tejido Adiposo/patología , Animales , Ácidos Araquidónicos/metabolismo , Dieta Alta en Grasa , Humanos , Inflamación/metabolismo , Inflamación/patología , Macrófagos/inmunología , Macrófagos/metabolismo , Ratones , Ratones Obesos , Obesidad/metabolismoRESUMEN
Mast cells originate from hematopoietic stem cells and undergo terminal maturation in the extravascular tissues, in which they are ultimately resident. Mast maturation, phenotype, and function are dictated by the local microenvironment, which has a significant influence on the ability of mast cells to recognize and respond to stimuli. Activation of mast cells can lead to the release of three distinct classes of mediators, including preformed mediators stored in secretory granules, newly transcribed cytokines and chemokines, and de novo-synthesized bioactive lipid mediators. It is currently recognized that bioactive lipids such as arachidonic acid metabolites (prostaglandins and leukotrienes) released from mast cells modulate innate and adaptive immune responses both directly and indirectly through communication with other microenvironmental immune cells or stroma cells. Moreover, mast cells express a variety of lipid receptors and, if activated by bioactive lipids such as arachidonic acid, ω3 fatty acids, lysophospholipids, and their metabolites, can alter the release and production of other mediators including histamine, cytokines, and chemokines, and thereby alter homeostatic or pathophysiological responses. This review focuses on newly identified functional aspects of bioactive lipids with regard to their immune regulation and functional outcomes in both homeostasis and allergic disease.
Asunto(s)
Inmunidad Innata/inmunología , Metabolismo de los Lípidos , Lípidos/inmunología , Mastocitos/inmunología , Mastocitos/metabolismo , Inmunidad Adaptativa/inmunología , Animales , Ácidos Araquidónicos/inmunología , Ácidos Araquidónicos/metabolismo , Microambiente Celular/inmunología , Liberación de Histamina , Homeostasis/inmunología , Humanos , Hipersensibilidad/inmunología , Leucotrienos/inmunología , Leucotrienos/metabolismo , Ratones , Prostaglandinas/inmunología , Prostaglandinas/metabolismoRESUMEN
Endogenous cannabinoids (endocannabinoids) are small molecules biosynthesized from membrane glycerophospholipid. Anandamide (AEA) is an endogenous intestinal cannabinoid that controls appetite and energy balance by engagement of the enteric nervous system through cannabinoid receptors. Here, we uncover a role for AEA and its receptor, cannabinoid receptor 2 (CB2), in the regulation of immune tolerance in the gut and the pancreas. This work demonstrates a major immunological role for an endocannabinoid. The pungent molecule capsaicin (CP) has a similar effect as AEA; however, CP acts by engagement of the vanilloid receptor TRPV1, causing local production of AEA, which acts through CB2. We show that the engagement of the cannabinoid/vanilloid receptors augments the number and immune suppressive function of the regulatory CX3CR1hi macrophages (MÏ), which express the highest levels of such receptors among the gut immune cells. Additionally, TRPV1-/- or CB2-/- mice have fewer CX3CR1hi MÏ in the gut. Treatment of mice with CP also leads to differentiation of a regulatory subset of CD4+ cells, the Tr1 cells, in an IL-27-dependent manner in vitro and in vivo. In a functional demonstration, tolerance elicited by engagement of TRPV1 can be transferred to naïve nonobese diabetic (NOD) mice [model of type 1 diabetes (T1D)] by transfer of CD4+ T cells. Further, oral administration of AEA to NOD mice provides protection from T1D. Our study unveils a role for the endocannabinoid system in maintaining immune homeostasis in the gut/pancreas and reveals a conversation between the nervous and immune systems using distinct receptors.
Asunto(s)
Ácidos Araquidónicos/inmunología , Receptor 1 de Quimiocinas CX3C/inmunología , Endocannabinoides/inmunología , Homeostasis , Inmunidad Mucosa , Intestinos/inmunología , Macrófagos/inmunología , Alcamidas Poliinsaturadas/inmunología , Animales , Cannabis/efectos adversos , Homeostasis/efectos de los fármacos , Homeostasis/inmunología , Tolerancia Inmunológica/efectos de los fármacos , Ratones , Ratones NoqueadosRESUMEN
Recent studies provide evidence that premature maternal decidual senescence resulting from heightened mTORC1 signaling is a cause of preterm birth (PTB). We show here that mice devoid of fatty acid amide hydrolase (FAAH) with elevated levels ofN-arachidonyl ethanolamide (anandamide), a major endocannabinoid lipid mediator, were more susceptible to PTB upon lipopolysaccharide (LPS) challenge. Anandamide is degraded by FAAH and primarily works by activating two G-protein-coupled receptors CB1 and CB2, encoded by Cnr1 and Cnr2, respectively. We found thatFaah(-/-)decidual cells progressively underwent premature senescence as marked by increased senescence-associated ß-galactosidase (SA-ß-Gal) staining and γH2AX-positive decidual cells. Interestingly, increased endocannabinoid signaling activated MAPK p38, but not p42/44 or mTORC1 signaling, inFaah(-/-)deciduae, and inhibition of p38 halted premature decidual senescence. We further showed that treatment of a long-acting anandamide in wild-type mice at midgestation triggered premature decidual senescence utilizing CB1, since administration of a CB1 antagonist greatly reduced the rate of PTB inFaah(-/-)females exposed to LPS. These results provide evidence that endocannabinoid signaling is critical in regulating decidual senescence and parturition timing. This study identifies a previously unidentified pathway in decidual senescence, which is independent of mTORC1 signaling.
Asunto(s)
Ácidos Araquidónicos/inmunología , Endocannabinoides/inmunología , Inflamación/complicaciones , Alcamidas Poliinsaturadas/inmunología , Nacimiento Prematuro/etiología , Nacimiento Prematuro/inmunología , Amidohidrolasas/genética , Amidohidrolasas/inmunología , Animales , Células Cultivadas , Decidua/citología , Decidua/inmunología , Femenino , Eliminación de Gen , Inflamación/genética , Inflamación/inmunología , Lipopolisacáridos/inmunología , Sistema de Señalización de MAP Quinasas , Masculino , Ratones , Nacimiento Prematuro/genética , Transducción de SeñalRESUMEN
In the retina, Müller glia is a dominant player of immune response. The HIV-1 transactivator viral protein (Tat) induces production of several neurotoxic cytokines in retinal cells. We show that HIV-1 clades Tat B and C act differentially on Müller glia, which is reflected in apoptosis, activation of cell death pathway components and pro-inflammatory cytokines. The harsher immune-mediated pathology of Tat B, as opposed to milder effects of Tat C, manifests at several signal transduction pathways, notably, MAPK, STAT, SOCS, the NFκB signalosome, and TTP. In activated cells, anandamide (AEA), acting as an immune-modulator, suppresses Tat B effect through MKP-1 but Tat C action via MEK-1. AEA lowers nuclear NF-κB and TAB2 for both variants while elevating IRAK1BP1 in activated Müller glia. Müller glia exposed to Tat shows enhanced PBMC attachment. Tat-induced increase in leukocyte adhesion to Müller cells can be mitigated by AEA, involving both CB receptors. This study identifies multiple signalling components that drive immune-mediated pathology and contribute to disease severity in HIV clades. We show that the protective effects of AEA occur at various stages in cytokine generation and are clade-dependant.
Asunto(s)
Ácidos Araquidónicos/inmunología , Citocinas/inmunología , Endocannabinoides/inmunología , Células Ependimogliales/inmunología , Inmunidad Innata/inmunología , Factores Inmunológicos/inmunología , Alcamidas Poliinsaturadas/inmunología , Productos del Gen tat del Virus de la Inmunodeficiencia Humana/farmacología , Adulto , Anciano , Ácidos Araquidónicos/farmacología , Células Cultivadas , Endocannabinoides/farmacología , Células Ependimogliales/efectos de los fármacos , Femenino , Regulación de la Expresión Génica/inmunología , Regulación de la Expresión Génica/efectos de la radiación , Humanos , Inmunidad Innata/efectos de los fármacos , Masculino , Persona de Mediana Edad , Alcamidas Poliinsaturadas/farmacología , Adulto JovenRESUMEN
2-Arachidonoyl-glycerol (2-AG) and arachidonyl-ethanolamide (AEA) are endocannabinoids that have been implicated in many physiologic disorders, including obesity, metabolic syndromes, hepatic diseases, pain, neurologic disorders, and inflammation. Their immunomodulatory effects are numerous and are not always mediated by cannabinoid receptors, reflecting the presence of an arachidonic acid (AA) molecule in their structure, the latter being the precursor of numerous bioactive lipids that are pro- or anti-inflammatory. 2-AG and AEA can thus serve as a source of AA but can also be metabolized by most eicosanoid biosynthetic enzymes, yielding additional lipids. In this regard, enhancing endocannabinoid levels by using endocannabinoid hydrolysis inhibitors is likely to augment the levels of these lipids that could regulate inflammatory cell functions. This review summarizes the metabolic pathways involved in the biosynthesis and metabolism of AEA and 2-AG, as well as the biologic effects of the 2-AG and AEA lipidomes in the regulation of inflammation.
Asunto(s)
Ácidos Araquidónicos/metabolismo , Células Dendríticas/metabolismo , Endocannabinoides/metabolismo , Glicéridos/metabolismo , Metabolismo de los Lípidos/inmunología , Linfocitos/metabolismo , Alcamidas Poliinsaturadas/metabolismo , Animales , Ácidos Araquidónicos/inmunología , Células Dendríticas/inmunología , Células Dendríticas/patología , Endocannabinoides/inmunología , Glicéridos/inmunología , Humanos , Inflamación/inmunología , Inflamación/metabolismo , Inflamación/patología , Hepatopatías/inmunología , Hepatopatías/metabolismo , Hepatopatías/patología , Linfocitos/inmunología , Linfocitos/patología , Síndrome Metabólico/inmunología , Síndrome Metabólico/metabolismo , Síndrome Metabólico/patología , Enfermedades Neurodegenerativas/inmunología , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/patología , Obesidad/inmunología , Obesidad/metabolismo , Obesidad/patología , Dolor/inmunología , Dolor/metabolismo , Dolor/patología , Ácidos Fosfatidicos/inmunología , Ácidos Fosfatidicos/metabolismo , Alcamidas Poliinsaturadas/inmunología , Receptores de Cannabinoides/inmunología , Receptores de Cannabinoides/metabolismoRESUMEN
Gαi-coupled chemoattractant receptors, such as the 5-oxo-6E,8Z,11Z,14Z-eicosatetraenoic acid (5-oxo-ETE) receptor (OXE-R), are able to switch on Gαißγ protein-dependent and ß-arrestin-related signaling traits. However, which of these signaling pathways are truly important for the chemoattractant functions in leukocytes is not clarified yet. As we recently reported, Gue1654 is a unique Gßγ-biased OXE-R antagonist having no inhibitory activity on Gαi-related signaling, which makes Gue1654 an unprecedented tool for assessing the involvement of G protein subunits in chemoattractant receptor function. ß-arrestin2 recruitment was studied in OXE-R-overexpressing HEK293 cells using bioluminescence resonance energy transfer assays. Activation of leukocytes was assessed by flow cytometric assays and by immunofluorescence microscopy. Leukocyte capture to endothelial cells was addressed under physiological flow conditions. We found that Gue1654 blocks ß-arrestin2 recruitment in HEK293 cells overexpressing OXE-R and ERK1/2 phosphorylation in human eosinophils and neutrophils. Furthermore, Gue1654 was able to prevent several 5-oxo-ETE-triggered functional events in eosinophils and neutrophils, such as activation of CD11b/CD18 integrins, oxidative burst, actin polymerization, and interaction with endothelial cells. In addition, Gue1654 completely prevented 5-oxo-ETE-induced Ca(2+) flux and chemotaxis of human primary monocytes. All of these leukocyte responses to 5-oxo-ETE, except ERK1/2 phosphorylation and oxidative burst, were likewise prevented by pertussis toxin. Therefore, we conclude that chemoattractant receptors require Gαi subunits only as adaptors to transactivate the Gßγ heteromers, which then act responsible for cell activation. Finally, our data characterize Gue1654 as a non-Gαi-biased antagonist of OXE-R that provides a new basis for therapeutic intervention in inflammatory diseases that involve activation of eosinophils, neutrophils, and monocytes.
Asunto(s)
Bencenoacetamidas/farmacología , Benzotiazoles/farmacología , Eosinófilos/inmunología , Subunidades alfa de la Proteína de Unión al GTP/inmunología , Monocitos/inmunología , Activación Neutrófila/inmunología , Neutrófilos/inmunología , Receptores Eicosanoides/antagonistas & inhibidores , Ácidos Araquidónicos/inmunología , Arrestinas/inmunología , Antígeno CD11b/inmunología , Antígenos CD18/inmunología , Calcio/inmunología , Quimiotaxis/efectos de los fármacos , Quimiotaxis/inmunología , Eosinófilos/citología , Femenino , Subunidades alfa de la Proteína de Unión al GTP/genética , Células HEK293 , Humanos , Masculino , Proteína Quinasa 1 Activada por Mitógenos/inmunología , Proteína Quinasa 3 Activada por Mitógenos/inmunología , Monocitos/citología , Activación Neutrófila/efectos de los fármacos , Neutrófilos/citología , Fosforilación/efectos de los fármacos , Fosforilación/inmunología , Receptores Eicosanoides/inmunología , beta-ArrestinasRESUMEN
How tissue damage is detected to induce inflammatory responses is unclear. Most studies have focused on damage signals released by cell breakage and necrosis. Whether tissues use other cues in addition to cell lysis to detect that they are damaged is unknown. We find that osmolarity differences between interstitial fluid and the external environment mediate rapid leukocyte recruitment to sites of tissue damage in zebrafish by activating cytosolic phospholipase a2 (cPLA2) at injury sites. cPLA2 initiates the production of non-canonical arachidonate metabolites that mediate leukocyte chemotaxis through a 5-oxo-ETE receptor (OXE-R). Thus, tissues can detect damage through direct surveillance of barrier integrity, with cell swelling probably functioning as a pro-inflammatory intermediate in the process.
Asunto(s)
Quimiotaxis de Leucocito/inmunología , Larva/inmunología , Leucocitos/inmunología , Ósmosis , Heridas y Lesiones/inmunología , Pez Cebra/inmunología , Animales , Ácidos Araquidónicos/inmunología , Ácidos Araquidónicos/metabolismo , Factores Quimiotácticos/inmunología , Factores Quimiotácticos/metabolismo , Citosol/inmunología , Citosol/metabolismo , Líquido Extracelular/inmunología , Líquido Extracelular/metabolismo , Espacio Extracelular/inmunología , Espacio Extracelular/metabolismo , Regulación de la Expresión Génica , Inmunidad Innata , Rayos Láser , Leucocitos/patología , Concentración Osmolar , Fosfolipasas A2 Citosólicas/genética , Fosfolipasas A2 Citosólicas/inmunología , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/inmunología , Transducción de Señal , Heridas y Lesiones/patologíaRESUMEN
The endocannabinoid 2-AG is highly susceptible to its hydrolysis into AA, which activates neutrophils through de novo LTB(4) biosynthesis, independently of CB activation. In this study, we show that 2-AG and AA stimulate neutrophils to release antimicrobial effectors. Supernatants of neutrophils activated with nanomolar concentrations of 2-AG and AA indeed inhibited the infectivity of HSV-1 and RSV. Additionally, the supernatants of 2-AG- and AA-stimulated neutrophils strongly impaired the growth of Escherichia coli and Staphylococcus aureus. This correlated with the release of a large amount (micrograms) of α-defensins, as well as a limited amount (nanograms) of LL-37. All the effects of AA and 2-AG mentioned above were prevented by inhibiting LTB(4) biosynthesis or by blocking BLT(1). Importantly, neither CB(2) receptor agonists nor antagonists could mimic nor prevent the effects of 2-AG, respectively. In fact, qPCR data show that contaminating eosinophils express â¼100-fold more CB(2) receptor mRNA than purified neutrophils, suggesting that CB(2) receptor expression by human neutrophils is limited and that contaminating eosinophils are likely responsible for the previously documented CB(2) expression by freshly isolated human neutrophils. The rapid conversion of 2-AG to AA and their subsequent metabolism into LTB(4) promote 2-AG and AA as multifunctional activators of neutrophils, mainly exerting their effects by activating the BLT(1). Considering that nanomolar concentrations of AA or 2-AG were sufficient to impair viral infectivity, this suggests potential physiological roles for 2-AG and AA as regulators of host defense in vivo.
Asunto(s)
Antiinfecciosos/metabolismo , Ácido Araquidónico/inmunología , Ácidos Araquidónicos/inmunología , Endocannabinoides/inmunología , Escherichia coli/inmunología , Glicéridos/inmunología , Herpesvirus Humano 1/inmunología , Neutrófilos/inmunología , Virus Sincitiales Respiratorios/inmunología , Staphylococcus aureus/inmunología , Antiinfecciosos/inmunología , Ácido Araquidónico/farmacología , Ácidos Araquidónicos/farmacología , Línea Celular , Endocannabinoides/farmacología , Glicéridos/farmacología , Humanos , Activación Neutrófila/inmunología , Neutrófilos/efectos de los fármacos , Neutrófilos/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
BACKGROUND: Cannabinoid (CB) 2 is expressed on immune and inflammatory cells. Identification of 2-arachidonyl glycerol (2-AG) and anandamide as endogenous CB2 ligands has allowed investigations of the roles of CB2 and its endogenous ligand system in inflammatory cells. However, the roles of this receptor-ligand system in inflammatory and allergic immune responses in vivo have not been fully elucidated. METHODS: Two mouse allergy models, namely ear dermatitis induced by 2,4-dinitrofluorobenzene and allergic bronchitis induced by ovalbumin, were analyzed for 2-AG amounts in allergic tissues, with reference to allergic and inflammatory symptoms. To investigate the gene expression via CB2 in inflammatory cells, human promyelocytic HL-60 cells were stimulated by the CB2 ligand 2-AG ether and analyzed using a DNA microarray. RESULTS: In the ear dermatitis model, the 2-AG amount increased upon serial 2,4-dinitrofluorobenzene challenges and was correlated with ear weight gain. The increased ear thickness in this allergy model was clearly suppressed in CB2 knockout mice, suggesting that the generated endogenous CB2 ligands induce ear thickness through aberrant inflammatory responses and remodeling mediated via CB2. In the allergic bronchitis model, the 2-AG level in bronchoalveolar lavage was increased and sustained during the elevation of inflammatory cell infiltration. The DNA microarray analysis of human HL-60 cells revealed that 2-AG ether induced expressions of not only inflammatory chemokines/cytokines but also of cell growth factors. CONCLUSION: Our data strongly suggest that endogenous CB2 ligands upregulated upon disease progression in allergic models are involved in aberrant alterations of both inflammatory responses and tissue cell growth.
Asunto(s)
Ácidos Araquidónicos/inmunología , Ácidos Araquidónicos/metabolismo , Cannabinoides/metabolismo , Endocannabinoides/inmunología , Endocannabinoides/metabolismo , Glicéridos/inmunología , Glicéridos/metabolismo , Hipersensibilidad/inmunología , Hipersensibilidad/metabolismo , Inflamación/inmunología , Inflamación/metabolismo , Receptor Cannabinoide CB2/inmunología , Receptor Cannabinoide CB2/metabolismo , Animales , Bronquitis/inmunología , Bronquitis/metabolismo , Quimiocinas/genética , Quimiocinas/metabolismo , Citocinas/genética , Citocinas/metabolismo , Dermatitis Alérgica por Contacto/genética , Dermatitis Alérgica por Contacto/inmunología , Dermatitis Alérgica por Contacto/metabolismo , Modelos Animales de Enfermedad , Femenino , Expresión Génica , Sustancias de Crecimiento/genética , Sustancias de Crecimiento/metabolismo , Células HL-60 , Humanos , Hipersensibilidad/genética , Inflamación/genética , Ligandos , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Receptor Cannabinoide CB2/deficiencia , Receptor Cannabinoide CB2/genéticaRESUMEN
Neutrophils spontaneously undergo apoptosis, which is associated with increased oxidative stress. We found that there is a dramatic shift in the formation of 5-lipoxygenase products during this process. Freshly isolated neutrophils rapidly convert leukotriene B(4) (LTB(4)) and 5-hydroxy-6,8,11,14-eicosatetraenoic acid (5-HETE) to their biologically inactive omega-oxidation products. However, omega-oxidation is impaired in neutrophils cultured for 24 h, when only 25% of the cells are nonapoptotic, resulting in the persistence of LTB(4) and a dramatic shift in 5-HETE metabolism to the potent granulocyte chemoattractant 5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE). The reduced omega-oxidation activity seems to be due to a reduction in LTB(4) 20-hydroxylase activity, whereas the increased 5-oxo-ETE formation is caused by a dramatic increase in the 5-hydroxyeicosanoid dehydrogenase cofactor NADP(+). NAD(+), but not NADPH, also increased, as did the GSSG/GSH ratio, indicative of oxidative stress. The changes in 5-HETE metabolism and pyridine nucleotides were inhibited by antiapoptotic agents (GM-CSF, forskolin) and antioxidants (diphenylene iodonium, catalase, deferoxamine), suggesting the involvement of H(2)O(2) and possibly other reactive oxygen species. These results suggest that in severe inflammation, aging neutrophils that have evaded rapid uptake by macrophages may produce increased amounts of the chemoattractants 5-oxo-ETE and LTB(4), resulting in delayed resolution or exacerbation of the inflammatory process.
Asunto(s)
Ácidos Araquidónicos/metabolismo , Factores Quimiotácticos/metabolismo , Ácidos Hidroxieicosatetraenoicos/metabolismo , Neutrófilos/fisiología , Piridinas/metabolismo , Oxidorreductasas de Alcohol/metabolismo , Antioxidantes/farmacología , Apoptosis/efectos de los fármacos , Araquidonato 5-Lipooxigenasa/inmunología , Araquidonato 5-Lipooxigenasa/metabolismo , Ácidos Araquidónicos/química , Ácidos Araquidónicos/inmunología , Biomimética , Células Cultivadas , Senescencia Celular/fisiología , Factores Quimiotácticos/química , Factores Quimiotácticos/inmunología , Colforsina/farmacología , Sistema Enzimático del Citocromo P-450/inmunología , Sistema Enzimático del Citocromo P-450/metabolismo , Familia 4 del Citocromo P450 , Humanos , Ácidos Hidroxieicosatetraenoicos/química , Leucotrieno B4/química , Leucotrieno B4/inmunología , Leucotrieno B4/metabolismo , NADP/metabolismo , Neutrófilos/efectos de los fármacos , Neutrófilos/patología , Oxidación-Reducción/efectos de los fármacos , Estrés Oxidativo , Piridinas/química , Piridinas/inmunología , Superóxido Dismutasa/químicaRESUMEN
Immune-mediated liver diseases including autoimmune and viral hepatitis are a major health problem worldwide. Natural cannabinoids such as Delta(9)-tetrahydrocannabinol (THC) effectively modulate immune cell function, and they have shown therapeutic potential in treating inflammatory diseases. We investigated the effects of THC in a murine model of concanavalin A (ConA)-induced hepatitis. Intraperitoneal administration of THC after ConA challenge inhibited hepatitis as shown by significant decrease in liver enzymes and reduced liver tissue injury. Furthermore, THC treatment resulted in significant suppression of crucial inflammatory cytokines in ConA-induced hepatitis. It is noteworthy that THC treatment in ConA-injected mice led to significant increase in absolute number of Forkhead helix transcription factor p3+ T regulatory cells in liver. We were surprised to find that select cannabinoid receptor (CB1 or CB2) agonists were not able to block hepatitis either independently or in combination. However, CB1/CB2 mixed agonists were able to efficiently attenuate hepatitis similar to THC. The modulatory effect of THC in ConA-induced hepatitis was reversed by both CB1 and CB2 antagonists. We also observed that endogenous cannabinoid anandamide was able to reduce hepatitis by suppressing cytokine levels. In addition, deficiency or inhibition of endocannabinoid hydrolyzing enzyme fatty acid amide hydrolase (FAAH), which leads to increased levels of endogenous cannabinoids, resulted in decreased liver injury upon ConA challenge. Our data demonstrate that targeting cannabinoid receptors using exogenous or endogenous cannabinoids and use of FAAH inhibitors may constitute novel therapeutic modalities to treat immune-mediated liver inflammation.
Asunto(s)
Ácidos Araquidónicos/farmacología , Moduladores de Receptores de Cannabinoides/farmacología , Dronabinol/farmacología , Hepatitis Autoinmune/tratamiento farmacológico , Alcamidas Poliinsaturadas/farmacología , Linfocitos T Reguladores/metabolismo , Alanina Transaminasa/metabolismo , Animales , Apoptosis/efectos de los fármacos , Ácidos Araquidónicos/inmunología , Aspartato Aminotransferasas/metabolismo , Moduladores de Receptores de Cannabinoides/inmunología , Células Cultivadas , Quimiocinas/análisis , Concanavalina A/toxicidad , Citocinas/análisis , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Dronabinol/inmunología , Endocannabinoides , Femenino , Hepatocitos/citología , Etiquetado Corte-Fin in Situ/métodos , Leucocitos/metabolismo , Hígado/citología , Hígado/enzimología , Hígado/metabolismo , Hígado/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Alcamidas Poliinsaturadas/inmunología , Receptores de Cannabinoides/inmunología , Factores de Tiempo , Resultado del TratamientoRESUMEN
Fibromyalgia (FM) is a common stress-related painful disorder. There is considerable evidence of neuroimmunologic alterations in FM which may be the consequence of chronic stress and pain or causally involved in the development of this disorder. The endocannabinoid system has been shown to play a pivotal role in mammalian nociception, is activated under stressful conditions and can be an important signaling pathway for immune modulation. The endocannabinoid system could therefore be involved in the complex pathophysiology of FM. We tested this hypothesis by evaluating the effects of stress hormones and the endocannabinoid anandamide on neutrophil function in patients with FM. We determined plasma levels of catecholamines, cortisol and anandamide in 22 patients with primary FM and 22 age- and sex-matched healthy controls. Neutrophil function was characterized by measuring the hydrogen peroxide (H2O2) release (oxidative stress) and the ingestion capabilities of neutrophils (microbicidal function). FM patients had significantly higher norepinephrine and anandamide plasma levels. Neutrophils of FM patients showed an elevated spontaneous H2O2 production. The ability of neutrophils to adhere was negatively correlated with serum cortisol levels. Adhesion and phagocytosis capabilities of neutrophils correlated positively with anandamide plasma levels. In conclusion, patients with FM might benefit from pharmacologic manipulation of endocannabinoid signaling which should be tested in controlled studies.
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Ácidos Araquidónicos/sangre , Moduladores de Receptores de Cannabinoides/sangre , Epinefrina/sangre , Fibromialgia/sangre , Neutrófilos/metabolismo , Norepinefrina/sangre , Alcamidas Poliinsaturadas/sangre , Ácidos Araquidónicos/inmunología , Ácidos Araquidónicos/metabolismo , Moduladores de Receptores de Cannabinoides/inmunología , Moduladores de Receptores de Cannabinoides/metabolismo , Estudios de Casos y Controles , Endocannabinoides , Femenino , Fibromialgia/inmunología , Fibromialgia/metabolismo , Humanos , Peróxido de Hidrógeno/metabolismo , Masculino , Persona de Mediana Edad , Neutrófilos/inmunología , Estrés Oxidativo , Fagocitosis , Alcamidas Poliinsaturadas/inmunología , Alcamidas Poliinsaturadas/metabolismo , Receptor Cannabinoide CB2/metabolismo , Proyectos de Investigación , Índice de Severidad de la Enfermedad , Encuestas y Cuestionarios , Zimosan/metabolismoRESUMEN
Cannabinoid receptors are expressed in macrophages, but little is known of their roles. We here examined their involvement in phagocytosis. The presence of 2-arachidonylglycerol, an endocannabinoid, augmented the phagocytosis of zymosan by mouse macrophages, while the phagocytosis of Escherichia coli, Staphylococcus aureus, apoptotic cells or latex beads remained unaffected. An agonist of the cannabinoid receptors CB1 and CB2 also stimulated the phagocytosis of zymosan. The stimulatory effect of 2-arachidonylglycerol was abolished when phagocytosis reactions were carried out in the presence of an antagonist of CB2 but not of CB1. Furthermore, the phagocytosis of zymosan in the presence of 2-arachidonylglycerol was severely inhibited by the addition of a beta-glucan-containing carbohydrate or antibody neutralizing dectin-1, a beta-glucan-recognizing phagocytosis receptor. These results suggested that the activation of CB2 in macrophages leads to the stimulation of dectin-1-mediated phagocytosis.
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Macrófagos/inmunología , Proteínas de la Membrana/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Fagocitosis , Receptor Cannabinoide CB1/metabolismo , Receptor Cannabinoide CB2/metabolismo , Animales , Ácidos Araquidónicos/inmunología , Ácidos Araquidónicos/farmacología , Moduladores de Receptores de Cannabinoides/inmunología , Moduladores de Receptores de Cannabinoides/farmacología , Endocannabinoides , Femenino , Glicéridos/inmunología , Glicéridos/farmacología , Lectinas Tipo C , Macrófagos/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Fagocitosis/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/metabolismo , Receptor Cannabinoide CB1/agonistas , Receptor Cannabinoide CB2/agonistas , Receptor Cannabinoide CB2/inmunología , Zimosan/inmunología , beta-Glucanos/inmunología , beta-Glucanos/farmacologíaRESUMEN
Eicosanoid production by macrophages is an early response to microbial infection that promotes acute inflammation. The intracellular pathogen Listeria monocytogenes stimulates arachidonic acid release and eicosanoid production from resident mouse peritoneal macrophages through activation of group IVA cytosolic phospholipase A2 (cPLA2alpha). The ability of wild type L. monocytogenes (WTLM) to stimulate arachidonic acid release is partially dependent on the virulence factor listeriolysin O; however, WTLM and L. monocytogenes lacking listeriolysin O (DeltahlyLM) induce similar levels of cyclooxygenase 2. Arachidonic acid release requires activation of MAPKs by WTLM and DeltahlyLM. The attenuated release of arachidonic acid that is observed in TLR2-/- and MyD88-/- macrophages infected with WTLM and DeltahlyLM correlates with diminished MAPK activation. WTLM but not DeltahlyLM increases intracellular calcium, which is implicated in regulation of cPLA2alpha. Prostaglandin E2, prostaglandin I2, and leukotriene C4 are produced by cPLA2alpha+/+ but not cPLA2alpha-/- macrophages in response to WTLM and DeltahlyLM. Tumor necrosis factor (TNF)-alpha production is significantly lower in cPLA2alpha+/+ than in cPLA2alpha-/- macrophages infected with WTLM and DeltahlyLM. Treatment of infected cPLA2alpha+/+ macrophages with the cyclooxygenase inhibitor indomethacin increases TNFalpha production to the level produced by cPLA2alpha-/- macrophages implicating prostaglandins in TNFalpha down-regulation. Therefore activation of cPLA2alpha in macrophages may impact immune responses to L. monocytogenes.
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Toxinas Bacterianas/metabolismo , Fosfolipasas A2 Grupo IV/metabolismo , Proteínas de Choque Térmico/metabolismo , Proteínas Hemolisinas/metabolismo , Listeria monocytogenes , Listeriosis/enzimología , Activación de Macrófagos/fisiología , Macrófagos Peritoneales/enzimología , Receptor Toll-Like 2/metabolismo , Factores de Virulencia/metabolismo , Animales , Ácidos Araquidónicos/genética , Ácidos Araquidónicos/inmunología , Ácidos Araquidónicos/metabolismo , Toxinas Bacterianas/inmunología , Calcio/inmunología , Calcio/metabolismo , Señalización del Calcio/efectos de los fármacos , Señalización del Calcio/fisiología , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/inmunología , Ciclooxigenasa 2/metabolismo , Inhibidores de la Ciclooxigenasa/farmacología , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/fisiología , Activación Enzimática/efectos de los fármacos , Activación Enzimática/fisiología , Quinasas MAP Reguladas por Señal Extracelular/genética , Quinasas MAP Reguladas por Señal Extracelular/inmunología , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Fosfolipasas A2 Grupo IV/genética , Fosfolipasas A2 Grupo IV/inmunología , Proteínas de Choque Térmico/inmunología , Proteínas Hemolisinas/inmunología , Indometacina/farmacología , Listeria monocytogenes/inmunología , Listeriosis/genética , Listeriosis/inmunología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/fisiología , Activación de Macrófagos/efectos de los fármacos , Macrófagos Peritoneales/inmunología , Macrófagos Peritoneales/microbiología , Ratones , Ratones Endogámicos ICR , Ratones Noqueados , Factor 88 de Diferenciación Mieloide/genética , Factor 88 de Diferenciación Mieloide/inmunología , Factor 88 de Diferenciación Mieloide/metabolismo , Receptor Toll-Like 2/genética , Receptor Toll-Like 2/inmunología , Factor de Necrosis Tumoral alfa/biosíntesis , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/inmunología , Factores de Virulencia/inmunologíaRESUMEN
In this study we analysed the regulation of gene expression by arvanil and anandamide in human peripheral blood mononuclear cells (PBMCs) to clarify their immunosuppressive properties. PBMCs were activated, leading to CD36 down regulation, that was normalized by arvanil and anandamide. We used microarray technology to identify a regulatory pattern associated with cell proliferation in the presence of both substances. CD3-CD28 stimulated PBMCs showed a pattern of up-regulated and down-regulated genes after treatment with these substances. We selected and analysed several genes chosen by their function in the regulation of cell proliferation. We showed a transcriptional control of the CD36 gene by arvanil and anandamide associated with an increased protein expression, thus suggesting a possible role of CD36 in anandamide and arvanil anti-inflammatory pattern.