RESUMO
Respiratory viral infections represent a constant threat for human health and urge for a better understanding of the pulmonary immune response to prevent disease severity. Macrophages are at the center of pulmonary immunity, where they play a pivotal role in orchestrating beneficial and/or pathological outcomes during infection. Eicosanoids, the host bioactive lipid mediators, have re-emerged as important regulators of pulmonary immunity during respiratory viral infections. In this review, we summarize the current knowledge linking eicosanoids' and pulmonary macrophages' homeostatic and antimicrobial functions and discuss eicosanoids as emerging targets for immunotherapy in viral infection.
Assuntos
Eicosanoides , Macrófagos Alveolares , Eicosanoides/metabolismo , Eicosanoides/imunologia , Humanos , Macrófagos Alveolares/imunologia , Animais , Pulmão/imunologia , Pulmão/virologia , Viroses/imunologia , Infecções Respiratórias/imunologia , Infecções Respiratórias/virologiaRESUMO
The significant morbidity and mortality associated with severe acute respiratory syndrome coronavirus 2 infection has underscored the need for novel antiviral strategies. Lipids play essential roles in the viral life cycle. The lipid composition of cell membranes can influence viral entry by mediating fusion or affecting receptor conformation. Upon infection, viruses can reprogram cellular metabolism to remodel lipid membranes and fuel the production of new virions. Furthermore, several classes of lipid mediators, including eicosanoids and sphingolipids, can regulate the host immune response to viral infection. Here, we summarize the existing literature on the mechanisms through which these lipid mediators may regulate viral burden in COVID-19. Furthermore, we define the gaps in knowledge and identify the core areas in which lipids offer therapeutic promise for severe acute respiratory syndrome coronavirus 2.
Assuntos
COVID-19/imunologia , Membrana Celular/imunologia , Eicosanoides/imunologia , SARS-CoV-2/fisiologia , Esfingolipídeos/imunologia , Replicação Viral/imunologia , HumanosRESUMO
BACKGROUND: Eosinophilic asthma and nasal polyposis are hallmarks of aspirin-exacerbated respiratory disease (AERD), and IL-5 inhibition has been shown to provide therapeutic benefit. However, IL-5Rα is expressed on many cells in addition to eosinophils, and the mechanisms by which IL-5 inhibition leads to clinical benefit in eosinophilic asthma and nasal polyposis are unlikely to be due exclusively to antieosinophil effects. OBJECTIVE: We sought to identify the mechanisms by which anti-IL-5 treatment with mepolizumab improves respiratory inflammation in AERD. METHODS: The clinical characteristics, circulating granulocytes, nasal scraping transcripts, eosinophilic cationic protein, tryptase, and antibody levels, and urinary and nasal eicosanoid levels were measured for 18 subjects with AERD who were taking mepolizumab and compared with those of 18 matched subjects with AERD who were not taking mepolizumab. RESULTS: Subjects taking mepolizumab had significantly fewer peripheral blood eosinophils and basophils, and those cells that remained had higher surface CRTH2 expression than did the cells from subjects not taking mepolizumab. Nasal prostaglandin F2α, prostaglandin D2 metabolites, leukotriene B4, and thromboxane levels were lower in subjects taking mepolizumab, as were urinary levels of tetranor-prostaglandin D2 and leukotriene E4. The nasal epithelial cell transcripts that were overexpressed among subjects with AERD who were taking mepolizumab were enriched for genes involved in tight junction formation and cilium organization. Nasal and urinary prostaglandin E2, tryptase, and antibody levels were not different between the 2 groups. CONCLUSION: IL-5 inhibition in AERD decreases production of inflammatory eicosanoids and upregulates tight junction-associated nasal epithelial cell transcripts, likely due to decreased IL-5 signaling on tissue mast cells, eosinophils, and epithelial cells. These direct effects on multiple relevant immune cells contribute to the mechanism of benefit afforded by mepolizumab.
Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Asma Induzida por Aspirina , Basófilos , Eosinófilos , Pólipos Nasais , Adolescente , Adulto , Idoso , Asma Induzida por Aspirina/tratamento farmacológico , Asma Induzida por Aspirina/imunologia , Asma Induzida por Aspirina/urina , Basófilos/imunologia , Basófilos/patologia , Eicosanoides/imunologia , Eicosanoides/urina , Eosinófilos/imunologia , Eosinófilos/patologia , Feminino , Humanos , Interleucina-5/imunologia , Subunidade alfa de Receptor de Interleucina-5/imunologia , Masculino , Pessoa de Meia-Idade , Pólipos Nasais/tratamento farmacológico , Pólipos Nasais/imunologia , Pólipos Nasais/urinaRESUMO
BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can lead to a variety of clinical outcomes, ranging from the absence of symptoms to severe acute respiratory disease and ultimately death. A feature of patients with severe coronavirus disease 2019 (COVID-19) is the abundance of inflammatory cytokines in the blood. Elevated levels of cytokines are predictive of infection severity and clinical outcome. In contrast, studies aimed at defining the driving forces behind the inflammation in lungs of subjects with severe COVID-19 remain scarce. OBJECTIVE: Our aim was to analyze and compare the plasma and bronchoalveolar lavage (BAL) fluids of patients with severe COVID-19 (n = 45) for the presence of cytokines and lipid mediators of inflammation (LMIs). METHODS: Cytokines were measured by using Luminex multiplex assay, and LMIs were measured by using liquid chromatography-tandem mass spectrometry. RESULTS: We revealed high concentrations of numerous cytokines, chemokines, and LMIs in the BAL fluid of patients with severe COVID-19. Of the 13 most abundant mediators in BAL fluid, 11 were chemokines, with CXCL1 and CXCL8 being 200 times more abundant than IL-6 and TNF-α. Eicosanoid levels were also elevated in the lungs of subjects with severe COVID-19. Consistent with the presence chemotactic molecules, BAL fluid samples were enriched for neutrophils, lymphocytes, and eosinophils. Inflammatory cytokines and LMIs in plasma showed limited correlations with those present in BAL fluid, arguing that circulating inflammatory molecules may not be a reliable proxy of the inflammation occurring in the lungs of patients with severe COVID-19. CONCLUSIONS: Our findings indicate that hyperinflammation of the lungs of patients with severe COVID-19 is fueled by excessive production of chemokines and eicosanoids. Therapeutic strategies to dampen inflammation in patients with COVID-19 should be tailored accordingly.
Assuntos
COVID-19/imunologia , Citocinas/imunologia , Eicosanoides/imunologia , Inflamação/imunologia , Pulmão/imunologia , SARS-CoV-2 , Adulto , Idoso , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , COVID-19/sangue , Citocinas/sangue , Feminino , Humanos , Inflamação/sangue , Pulmão/citologia , Linfócitos/imunologia , Masculino , Pessoa de Meia-Idade , Neutrófilos/imunologia , Índice de Gravidade de DoençaRESUMO
This paper is focused on eicosanoid signaling in insect immunology. We begin with eicosanoid biosynthesis through the actions of phospholipase A2, responsible for hydrolyzing the C18 polyunsaturated fatty acid, linoleic acid (18:2n-6), from cellular phospholipids, which is subsequently converted into arachidonic acid (AA; 20:4n-6) via elongases and desaturases. The synthesized AA is then oxygenated into one of three groups of eicosanoids, prostaglandins (PGs), epoxyeicosatrienoic acids (EETs) and lipoxygenase products. We mark the distinction between mammalian cyclooxygenases and insect peroxynectins, both of which convert AA into PGs. One PG, PGI2 (also called prostacyclin), is newly discovered in insects, as a negative regulator of immune reactions and a positive signal in juvenile development. Two new elements of insect PG biology are a PG dehydrogenase and a PG reductase, both of which enact necessary PG catabolism. EETs, which are produced from AA via cytochrome P450s, also act in immune signaling, acting as pro-inflammatory signals. Eicosanoids signal a wide range of cellular immune reactions to infections, invasions and wounding, including nodulation, cell spreading, hemocyte migration and releasing prophenoloxidase from oenocytoids, a class of lepidopteran hemocytes. We briefly review the relatively scant knowledge on insect PG receptors and note PGs also act in gut immunity and in humoral immunity. Detailed new information on PG actions in mosquito immunity against the malarial agent, Plasmodium berghei, has recently emerged and we treat this exciting new work. The new findings on eicosanoid actions in insect immunity have emerged from a very broad range of research at the genetic, cellular and organismal levels, all taking place at the international level.
Assuntos
Eicosanoides/genética , Insetos/genética , Fosfolipases A2/genética , Transdução de Sinais/genética , Animais , Ácido Araquidônico/genética , Ácido Araquidônico/imunologia , Eicosanoides/biossíntese , Eicosanoides/imunologia , Ácidos Graxos Dessaturases/genética , Ácidos Graxos Dessaturases/imunologia , Hemócitos/enzimologia , Insetos/imunologia , Insetos/metabolismo , Lipoxigenase/genética , Lipoxigenase/imunologia , Mamíferos/genética , Mamíferos/imunologia , Fosfolipases A2/imunologia , Fator de Ativação de Plaquetas/análogos & derivados , Fator de Ativação de Plaquetas/genética , Fator de Ativação de Plaquetas/imunologia , Prostaglandina-Endoperóxido Sintases/genéticaRESUMO
The COVID-19 pandemic has affected more than 20 million people worldwide, with mortality exceeding 800,000 patients. Risk factors associated with severe disease and mortality include advanced age, hypertension, diabetes, and obesity. Each of these risk factors pathologically disrupts the lipidome, including immunomodulatory eicosanoid and docosanoid lipid mediators (LMs). We hypothesized that dysregulation of LMs may be a defining feature of the severity of COVID-19. By examining LMs and polyunsaturated fatty acid precursor lipids in serum from hospitalized COVID-19 patients, we demonstrate that moderate and severe disease are separated by specific differences in abundance of immune-regulatory and proinflammatory LMs. This difference in LM balance corresponded with decreased LM products of ALOX12 and COX2 and an increase LMs products of ALOX5 and cytochrome p450. Given the important immune-regulatory role of LMs, these data provide mechanistic insight into an immuno-lipidomic imbalance in severe COVID-19.
Assuntos
COVID-19 , Eicosanoides , Lipidômica , SARS-CoV-2 , Adulto , Idoso , Idoso de 80 Anos ou mais , Araquidonato 12-Lipoxigenase/imunologia , Araquidonato 12-Lipoxigenase/metabolismo , Araquidonato 5-Lipoxigenase/imunologia , Araquidonato 5-Lipoxigenase/metabolismo , Biomarcadores/sangue , COVID-19/sangue , COVID-19/imunologia , Ciclo-Oxigenase 2/imunologia , Ciclo-Oxigenase 2/metabolismo , Eicosanoides/sangue , Eicosanoides/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , SARS-CoV-2/imunologia , SARS-CoV-2/metabolismoRESUMO
OBJECTIVE: To review the latest discoveries regarding the role of tuft cells in the pathogenesis of chronic rhinosinusitis (CRS) with nasal polyposis and asthma. DATA SOURCES: Reviews and primary research manuscripts were identified from PubMed, Google, and bioRxiv using the search words airway epithelium, nasal polyposis, CRS or asthma and chemoreceptor cell, solitary chemosensory cell, brush cell, microvillus cell, and tuft cell. STUDY SELECTIONS: Studies were selected on the basis of novelty and likely relevance to the functions of tuft cells in chronic inflammatory diseases in the upper and lower airways. RESULTS: Tuft cells coordinate a variety of immune responses throughout the body. After the activation of bitter-taste receptors, tuft cells coordinate the secretion of antimicrobial products by adjacent epithelial cells and initiate the calcium-dependent release of acetylcholine resulting in neurogenic inflammation, including mast cell degranulation and plasma extravasation. Tuft cells are also the dominant source of interleukin-25 and a significant source of cysteinyl leukotrienes that play a role in initiating inflammatory processes in the airway. Tuft cells have also been found to seem de novo in the distal airway after a viral infection, implicating these cells in dysplastic remodeling in the distal lung in the pathogenesis of asthma. CONCLUSION: Tuft cells bridge innate and adaptive immunes responses and play an upstream role in initiating type 2 inflammation in the upper and possibly the lower airway. The role of tuft cells in respiratory pathophysiology must be further investigated, because tuft cells are putative high-value therapeutic targets for novel therapeutics in CRS with nasal polyps and asthma.
Assuntos
Asma/imunologia , Células Epiteliais/imunologia , Pólipos Nasais/imunologia , Sistema Respiratório/citologia , Rinite/imunologia , Sinusite/imunologia , Acetilcolina/imunologia , Animais , Doença Crônica , Eicosanoides/imunologia , Humanos , Interleucina-17/imunologia , Sistema Respiratório/imunologiaRESUMO
Intestinal ischemia/reperfusion (I/R)-induced injury is an inflammatory response with significant morbidity and mortality. The early inflammatory response includes neutrophil infiltration. However, the majority of rodent studies utilize male mice despite a sexual dimorphism in intestinal I/R-related diseases. We hypothesized that sex may alter inflammation by changing neutrophil infiltration and eicosanoid production. To test this hypothesis, male and female C57Bl/6 mice were subjected to sham treatment or 30 min intestinal ischemia followed by a time course of reperfusion. We demonstrate that compared to male mice, females sustain significantly less intestinal I/R-induced tissue damage and produced significant LTB4 concentrations. Male mice release PGE2. Finally, treatment with a COX-2 specific inhibitor, NS-398, attenuated I/R-induced injury, total peroxidase level, and PGE2 production in males, but not in similarly treated female mice. Thus, I/R-induced eicosanoid production and neutrophil infiltration varies between sexes suggesting that distinct therapeutic intervention may be needed in clinical ischemic diseases.
Assuntos
Dinoprostona/imunologia , Leucotrieno B4/imunologia , Mesentério/irrigação sanguínea , Traumatismo por Reperfusão/imunologia , Caracteres Sexuais , Animais , Complemento C5a/imunologia , Citocinas/imunologia , Eicosanoides/imunologia , Feminino , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Intestino Delgado/imunologia , Intestino Delgado/patologia , Macrófagos/imunologia , Masculino , Camundongos Endogâmicos C57BL , Infiltração de Neutrófilos , Peroxidase/imunologia , Traumatismo por Reperfusão/patologiaRESUMO
This article describes the pathways of eicosanoid synthesis, eicosanoid receptors, the action of eicosanoids in different physiological systems, the roles of eicosanoids in selected diseases, and the major inhibitors of eicosanoid synthesis and action. Eicosanoids are oxidised derivatives of 20-carbon polyunsaturated fatty acids (PUFAs) formed by the cyclooxygenase (COX), lipoxygenase (LOX) and cytochrome P450 (cytP450) pathways. Arachidonic acid (ARA) is the usual substrate for eicosanoid synthesis. The COX pathways form prostaglandins (PGs) and thromboxanes (TXs), the LOX pathways form leukotrienes (LTs) and lipoxins (LXs), and the cytP450 pathways form various epoxy, hydroxy and dihydroxy derivatives. Eicosanoids are highly bioactive acting on many cell types through cell membrane G-protein coupled receptors, although some eicosanoids are also ligands for nuclear receptors. Because they are rapidly catabolised, eicosanoids mainly act locally to the site of their production. Many eicosanoids have multiple, sometimes pleiotropic, effects on inflammation and immunity. The most widely studied is PGE2. Many eicosanoids have roles in the regulation of the vascular, renal, gastrointestinal and female reproductive systems. Despite their vital role in physiology, eicosanoids are often associated with disease, including inflammatory disease and cancer. Inhibitors have been developed that interfere with the synthesis or action of various eicosanoids and some of these are used in disease treatment, especially for inflammation.
Assuntos
Eicosanoides/biossíntese , Eicosanoides/imunologia , Ácido Araquidônico/metabolismo , Artrite Reumatoide/metabolismo , Asma/metabolismo , Inibidores de Ciclo-Oxigenase/farmacologia , Eicosanoides/antagonistas & inibidores , Humanos , Doenças Inflamatórias Intestinais/metabolismo , Lipoxigenase/metabolismo , NADPH-Ferri-Hemoproteína Redutase/metabolismo , Neoplasias/metabolismo , Prostaglandina-Endoperóxido Sintases/metabolismo , Receptores Eicosanoides/metabolismoRESUMO
Toxic environmental carcinogens promote cancer via genotoxic and nongenotoxic pathways, but nongenetic mechanisms remain poorly characterized. Carcinogen-induced apoptosis may trigger escape from dormancy of microtumors by interfering with inflammation resolution and triggering an endoplasmic reticulum (ER) stress response. While eicosanoid and cytokine storms are well-characterized in infection and inflammation, they are poorly characterized in cancer. Here, we demonstrate that carcinogens, such as aflatoxin B1 (AFB1), induce apoptotic cell death and the resulting cell debris stimulates hepatocellular carcinoma (HCC) tumor growth via an "eicosanoid and cytokine storm." AFB1-generated debris up-regulates cyclooxygenase-2 (COX-2), soluble epoxide hydrolase (sEH), ER stress-response genes including BiP, CHOP, and PDI in macrophages. Thus, selective cytokine or eicosanoid blockade is unlikely to prevent carcinogen-induced cancer progression. Pharmacological abrogation of both the COX-2 and sEH pathways by PTUPB prevented the debris-stimulated eicosanoid and cytokine storm, down-regulated ER stress genes, and promoted macrophage phagocytosis of debris, resulting in suppression of HCC tumor growth. Thus, inflammation resolution via dual COX-2/sEH inhibition is an approach to prevent carcinogen-induced cancer.
Assuntos
Citocinas/metabolismo , Eicosanoides/metabolismo , Neoplasias Hepáticas/metabolismo , Aflatoxina B1/efeitos adversos , Animais , Apoptose , Carcinogênese/metabolismo , Carcinógenos/metabolismo , Carcinoma Hepatocelular/metabolismo , Linhagem Celular , Ciclo-Oxigenase 2/metabolismo , Citocinas/imunologia , Progressão da Doença , Eicosanoides/imunologia , Epóxido Hidrolases/metabolismo , Células Hep G2 , Humanos , Inflamação/metabolismo , Neoplasias Hepáticas/fisiopatologia , Macrófagos/metabolismo , Camundongos , Processos NeoplásicosRESUMO
Rheumatoid arthritis, asthma, allergic rhinitis and many other disorders related to an aberrant immune response have a higher incidence and severity in women than in men. Emerging evidences from scientific studies indicate that the activity of the immune system is superior in females and that androgens may act as "immunosuppressive" molecules with inhibitory effects on inflammatory reactions. Among the multiple factors that contribute to the inflammatory response, lipid mediators (LM), produced from polyunsaturated fatty acids, represent a class of bioactive small molecules with pivotal roles in the onset, maintenance and resolution of inflammation. LM encompass pro-inflammatory eicosanoids and specialized pro-resolving mediators (SPM) that coexist in a tightly regulated balance necessary for the return to homeostasis. Innate immune cells including neutrophils, monocytes and macrophages possess high capacities to generate distinct LM. In the last decades it became more and more evident that sex represents an important variable in the regulation of inflammation where sex hormones play crucial roles. Recent findings showed that the biosynthesis of inflammation-related LM is sex-biased and that androgens impact LM formation with consequences not only for pathophysiology but also for pharmacotherapy. Here, we review the modulation of the inflammatory response by sex and androgens with a specific focus on LM pathways. In particular, we highlight the impact of androgens on the biosynthetic pathway of inflammation-related eicosanoids in innate immune cells.
Assuntos
Androgênios/metabolismo , Eicosanoides/metabolismo , Imunidade Inata/imunologia , Mediadores da Inflamação/metabolismo , Androgênios/imunologia , Animais , Eicosanoides/imunologia , Feminino , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Mediadores da Inflamação/imunologia , Lipídeos/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Monócitos/imunologia , Monócitos/metabolismo , Neutrófilos/imunologia , Neutrófilos/metabolismoRESUMO
Severe coronavirus disease (COVID-19) is characterized by pulmonary hyper-inflammation and potentially life-threatening "cytokine storms". Controlling the local and systemic inflammatory response in COVID-19 may be as important as anti-viral therapies. Endogenous lipid autacoid mediators, referred to as eicosanoids, play a critical role in the induction of inflammation and pro-inflammatory cytokine production. SARS-CoV-2 may trigger a cell death ("debris")-induced "eicosanoid storm", including prostaglandins and leukotrienes, which in turn initiates a robust inflammatory response. A paradigm shift is emerging in our understanding of the resolution of inflammation as an active biochemical process with the discovery of novel endogenous specialized pro-resolving lipid autacoid mediators (SPMs), such as resolvins. Resolvins and other SPMs stimulate macrophage-mediated clearance of debris and counter pro-inflammatory cytokine production, a process called inflammation resolution. SPMs and their lipid precursors exhibit anti-viral activity at nanogram doses in the setting of influenza without being immunosuppressive. SPMs also promote anti-viral B cell antibodies and lymphocyte activity, highlighting their potential use in the treatment of COVID-19. Soluble epoxide hydrolase (sEH) inhibitors stabilize arachidonic acid-derived epoxyeicosatrienoic acids (EETs), which also stimulate inflammation resolution by promoting the production of pro-resolution mediators, activating anti-inflammatory processes, and preventing the cytokine storm. Both resolvins and EETs also attenuate pathological thrombosis and promote clot removal, which is emerging as a key pathology of COVID-19 infection. Thus, both SPMs and sEH inhibitors may promote the resolution of inflammation in COVID-19, thereby reducing acute respiratory distress syndrome (ARDS) and other life-threatening complications associated with robust viral-induced inflammation. While most COVID-19 clinical trials focus on "anti-viral" and "anti-inflammatory" strategies, stimulating inflammation resolution is a novel host-centric therapeutic avenue. Importantly, SPMs and sEH inhibitors are currently in clinical trials for other inflammatory diseases and could be rapidly translated for the management of COVID-19 via debris clearance and inflammatory cytokine suppression. Here, we discuss using pro-resolution mediators as a potential complement to current anti-viral strategies for COVID-19.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Antivirais/uso terapêutico , Betacoronavirus/imunologia , Infecções por Coronavirus/tratamento farmacológico , Síndrome da Liberação de Citocina/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Síndrome do Desconforto Respiratório/terapia , Anti-Inflamatórios não Esteroides/farmacologia , Betacoronavirus/isolamento & purificação , COVID-19 , Ensaios Clínicos como Assunto , Infecções por Coronavirus/complicações , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Síndrome da Liberação de Citocina/imunologia , Citocinas/imunologia , Citocinas/metabolismo , Eicosanoides/imunologia , Eicosanoides/metabolismo , Epóxido Hidrolases/antagonistas & inibidores , Epóxido Hidrolases/metabolismo , Humanos , Macrófagos/imunologia , Macrófagos/metabolismo , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Alvéolos Pulmonares/imunologia , Alvéolos Pulmonares/metabolismo , Alvéolos Pulmonares/virologia , Síndrome do Desconforto Respiratório/imunologia , SARS-CoV-2RESUMO
Lipid droplets are fat storage organelles present in most eukaryotic cells. They consist of a neutral lipid core containing mostly triglycerides and sterol esters and covered by a monolayer of phospholipids, wherein numerous proteins are embedded. In the cell, lipid droplets have a dynamic life cycle, rapidly altering their size, location, lipid and protein composition in response to environmental stimuli and cell state. Lipid droplets are primarily involved in the coordination of lipid metabolism with cellular requirements for energy production, membrane homeostasis and cell growth. However, they are also directly or indirectly engaged in signalling pathways. On the one hand, lipid droplets sequester lipids and proteins thereby limiting their availability for participation in signalling pathways. On the other hand, the lipolytic machinery provides a highly regulated, on-demand source of signalling lipids: lipids derived from their neutral lipid core, or the phospholipid monolayer, directly act as signalling mediators or are converted into ones. In fact, emerging studies suggest that these organelles are essential for various cellular stress response mechanisms, including inflammation and immunity, acting as hubs that integrate metabolic and inflammatory processes. Here, we discuss the ways in which lipid droplets regulate the availability of fatty acids for the activation of signalling pathways and for the production of polyunsaturated fatty acid-derived lipid mediators. We focus in particular on recent discoveries in immune cells and adipose tissue that have revealed an intricate relationship between lipid droplets and inflammatory signalling and may also be relevant for other tissues and various human diseases.
Assuntos
Tecido Adiposo/metabolismo , Eicosanoides/metabolismo , Gotículas Lipídicas/metabolismo , Metabolismo dos Lipídeos/genética , Fosfolipídeos/metabolismo , Triglicerídeos/metabolismo , Tecido Adiposo/imunologia , Animais , Ácidos Docosa-Hexaenoicos/imunologia , Ácidos Docosa-Hexaenoicos/metabolismo , Eicosanoides/imunologia , Regulação da Expressão Gênica , Homeostase/genética , Homeostase/imunologia , Humanos , Inflamação , Lipase/genética , Lipase/imunologia , Gotículas Lipídicas/imunologia , Metabolismo dos Lipídeos/imunologia , Fosfolipases/genética , Fosfolipases/imunologia , Fosfolipídeos/imunologia , Transdução de Sinais , Receptores Toll-Like/genética , Receptores Toll-Like/imunologia , Triglicerídeos/imunologiaRESUMO
The participation of cytokines and chemokines in Plasmodium vivax malaria (Pv-malaria) activates the immune response and thus causes the production of several inflammatory mediators. This process is already well-established, but little is known about eicosanoids in malaria physiopathology, especially in regards to inflammation and immunity. Malaria is an acute febrile syndrome similar to any other less important infectious disease and people may self-medicate with any anti-inflammatory drugs in order to cease the recurrent symptoms of the disease. Based on this information, the study describes the eicosanoid profile and its possible influence on the production of cytokines and chemokines in P. vivax infections. In addition, we investigated the influence of self-medication with anti-inflammatory drugs in this immune profile. Twenty-three patients were included in the study, with or without self-medication by anti-inflammatory drugs prior to diagnosis. A total 12 individuals were selected for the control group. Eicosanoid profiles were quantified by HPLC-MS/MS, and cytokines and chemokines by flow cytometry and ELISA. The Pv-malaria infection significantly reduces the production of several lipid mediators, and its action is increased by self-medication. We observed that the eicosanoids we found derive from the lipoxygenase and cyclooxygenase pathways, and present positive and negative correlations with chemokines and cytokines in the follow-up of patients. Our data suggest that self-medication may interfere in the immunological characteristics in P. vivax infection and may modify the follow-up of the disease.
Assuntos
Eicosanoides/sangue , Malária Vivax/sangue , Malária Vivax/imunologia , Adulto , Anti-Inflamatórios/uso terapêutico , Citocinas/sangue , Citocinas/imunologia , Eicosanoides/imunologia , Feminino , Humanos , Malária Vivax/tratamento farmacológico , Masculino , Pessoa de Meia-IdadeRESUMO
Dermatological research is a major beneficiary of the rapidly developing advances in lipid analytic technology and of bioinformatic tools which help to decipher and interpret the accumulating big lipid data. At its interface with the environment, the epidermis develops a blend of lipids that constitutes the epidermal lipid barrier, essential for the protection from water loss and entry of dangerous noxae. Apart from their structural role in the barrier, novel intra- and inter-cellular signaling functions of lipids and their oxidation products have been uncovered in most cutaneous cell types over the last decades, and the discovery rate has been boosted by the advent of high resolution and -throughput mass spectrometric techniques. Our understanding of epidermal development has benefited from studies on fetal surface lipids, which appear to signal for adaptation to desiccation post partum, and from studies on the dynamics of epidermal lipids during adjustment to the atmosphere in the first months of life. At birth, external insults begin to challenge the skin and its lipids, and recent years have yielded ample insights into the dynamics of lipid synthesis and -oxdiation after UV exposure, and upon contact with sensitizers and irritants. Psoriasis and atopic dermatitis are the most common chronic inflammatory skin diseases, affecting at least 3% and 7% of the global population, respectively. Consequently, novel (redox-) lipidomic techniques have been applied to study systemic and topical lipid abnormalities in patient cohorts. These studies have refined the knowledge on eicosanoid signaling in both diseases, and have identified novel biomarkers and potential disease mediators, such as lipid antigens recognized by psoriatic T cells, as well as ceramide species, which specifically correlate with atopic dermatitis severity. Both biomarkers have yielded novel mechanistic insights. Finally, the technological progress has enabled studies to be performed that have monitored the consequences of diet, lifestyle, therapy and cosmetic intervention on the skin lipidome, highlighting the translational potential of (redox-) lipidomics in dermatology.
Assuntos
Acne Vulgar/metabolismo , Ceramidas/metabolismo , Dermatite Atópica/metabolismo , Eicosanoides/metabolismo , Lipidômica/tendências , Psoríase/metabolismo , Acne Vulgar/diagnóstico , Acne Vulgar/imunologia , Acne Vulgar/patologia , Adulto , Autoantígenos/imunologia , Autoantígenos/metabolismo , Biomarcadores/metabolismo , Ceramidas/imunologia , Criança , Dermatite Atópica/diagnóstico , Dermatite Atópica/imunologia , Dermatite Atópica/patologia , Eicosanoides/imunologia , Feto , Humanos , Metabolismo dos Lipídeos , Oxirredução , Psoríase/diagnóstico , Psoríase/imunologia , Psoríase/patologia , Transdução de Sinais , Pele/metabolismo , Pele/patologia , Linfócitos T/imunologia , Linfócitos T/patologiaRESUMO
Cryptococcus neoformans is one of the leading causes of invasive fungal infection in humans worldwide. C. neoformans uses macrophages as a proliferative niche to increase infective burden and avoid immune surveillance. However, the specific mechanisms by which C. neoformans manipulates host immunity to promote its growth during infection remain ill-defined. Here we demonstrate that eicosanoid lipid mediators manipulated and/or produced by C. neoformans play a key role in regulating pathogenesis. C. neoformans is known to secrete several eicosanoids that are highly similar to those found in vertebrate hosts. Using eicosanoid deficient cryptococcal mutants Δplb1 and Δlac1, we demonstrate that prostaglandin E2 is required by C. neoformans for proliferation within macrophages and in vivo during infection. Genetic and pharmacological disruption of host PGE2 synthesis is not required for promotion of cryptococcal growth by eicosanoid production. We find that PGE2 must be dehydrogenated into 15-keto-PGE2 to promote fungal growth, a finding that implicated the host nuclear receptor PPAR-γ. C. neoformans infection of macrophages activates host PPAR-γ and its inhibition is sufficient to abrogate the effect of 15-keto-PGE2 in promoting fungal growth during infection. Thus, we describe the first mechanism of reliance on pathogen-derived eicosanoids in fungal pathogenesis and the specific role of 15-keto-PGE2 and host PPAR-γ in cryptococcosis.
Assuntos
Cryptococcus neoformans/metabolismo , Dinoprostona/análogos & derivados , Eicosanoides/metabolismo , Animais , Animais Geneticamente Modificados , Técnicas de Cultura de Células , Criptococose/metabolismo , Cryptococcus neoformans/crescimento & desenvolvimento , Cryptococcus neoformans/patogenicidade , Dinoprostona/metabolismo , Dinoprostona/fisiologia , Modelos Animais de Doenças , Eicosanoides/imunologia , Interações Hospedeiro-Patógeno/fisiologia , Humanos , Macrófagos/microbiologia , PPAR gama/metabolismo , Virulência/fisiologia , Peixe-Zebra/microbiologiaRESUMO
BACKGROUND: Classical FcεRI-induced mast cell (MC) activation causes synthesis of arachidonic acid (AA)-derived eicosanoids (leukotriene [LT] C4, prostaglandin [PG] D2, and thromboxane A2), which mediate vascular leak, bronchoconstriction, and effector cell chemotaxis. Little is known about the significance and regulation of eicosanoid generation in response to nonclassical MC activation mechanisms. OBJECTIVES: We sought to determine the regulation and significance of MC-derived eicosanoids synthesized in response to IL-33, a cytokine critical to innate type 2 immunity. METHODS: We used an ex vivo model of mouse bone marrow-derived mast cells and an IL-33-dependent in vivo model of aspirin-exacerbated respiratory disease (AERD). RESULTS: IL-33 potently liberates AA and elicits LTC4, PGD2, and thromboxane A2 production by bone marrow-derived mast cells. Unexpectedly, the constitutive function of COX-1 is required for IL-33 to activate group IVa cytosolic phospholipase A2 with consequent AA release for synthesis of all eicosanoids, including CysLTs. In contrast, COX-1 was dispensable for FcεRI-driven CysLT production. Inhibition of COX-1 prevented IL-33-induced phosphorylation of extracellular signal-related kinase, an upstream effector of cytosolic phospholipase A2, which was restored by exogenous PGH2, implying that the effects of COX-1 required its catalytic function. Administration of a COX-1-selective antagonist to mice completely prevented the generation of both PGD2 and LTC4 in a model of AERD in which MC activation is IL-33 driven. CONCLUSIONS: MC-intrinsic COX-1 amplifies IL-33-induced activation in the setting of innate type 2 immunity and might help explain the phenomenon of therapeutic desensitization to aspirin by nonselective COX inhibitors in patients with AERD.
Assuntos
Asma Induzida por Aspirina/imunologia , Ciclo-Oxigenase 1/imunologia , MAP Quinases Reguladas por Sinal Extracelular/imunologia , Interleucina-33/imunologia , Mastócitos/imunologia , Proteínas de Membrana/imunologia , Animais , Células Cultivadas , Ciclo-Oxigenase 2/imunologia , Inibidores de Ciclo-Oxigenase/farmacologia , Eicosanoides/imunologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosfolipases A2 Citosólicas/imunologiaRESUMO
Allergic conjunctivitis (AC) is one of the most common ocular surface diseases in the world. In AC, T helper type 2 (Th2) immune responses play central roles in orchestrating inflammatory responses. However, the roles of lipid mediators in the onset and progression of AC remain to be fully explored. Although previous reports have shown the beneficial effects of supplementation of ω-3 fatty acids in asthma or atopic dermatitis, the underlying molecular mechanisms are poorly understood. In this study, a diet rich in ω-3 fatty acids alleviated AC symptoms in both early and late phases without affecting Th2 immune responses, but rather by altering the lipid mediator profiles. The ω-3 fatty acids completely suppressed scratching behavior toward the eyes, an allergic reaction provoked by itch. Although total serum IgE levels and the expression levels of Th2 cytokines and chemokines in the conjunctiva were not altered by ω-3 fatty acids, eosinophil infiltration into the conjunctiva was dramatically suppressed. The levels of ω-6-derived proinflammatory lipid mediators, including those with chemoattractant properties for eosinophils, were markedly reduced in the conjunctivae of ω-3 diet-fed mice. Dietary ω-3 fatty acids can alleviate a variety of symptoms of AC by altering the lipid mediator profile.-Hirakata, T., Lee, H.-C., Ohba, M., Saeki, K., Okuno, T., Murakami, A., Matsuda, A., Yokomizo, T. Dietary ω-3 fatty acids alter the lipid mediator profile and alleviate allergic conjunctivitis without modulating Th2 immune responses.
Assuntos
Conjuntivite Alérgica/imunologia , Ácidos Graxos Ômega-3/imunologia , Lipídeos/imunologia , Células Th2/imunologia , Animais , Asma/imunologia , Quimiocinas/imunologia , Citocinas/imunologia , Dieta/métodos , Eicosanoides/imunologia , Eosinófilos/imunologia , Feminino , Imunoglobulina E/imunologia , Camundongos , Camundongos Endogâmicos BALB CRESUMO
Asthma is a common lung disease affecting 300 million people worldwide. Allergic asthma is recognized as a prototypical Th2 disorder, orchestrated by an aberrant adaptive CD4+ T helper (Th2/Th17) cell immune response against airborne allergens, that leads to eosinophilic inflammation, reversible bronchoconstriction, and mucus overproduction. Other forms of asthma are controlled by an eosinophil-rich innate ILC2 response driven by epithelial damage, whereas in some patients with more neutrophilia, the disease is driven by Th17 cells. Dendritic cells (DCs) and macrophages are crucial regulators of type 2 immunity in asthma. Numerous lipid mediators including the eicosanoids prostaglandins and leukotrienes influence key functions of these cells, leading to either pro- or anti-inflammatory effects on disease outcome. In this review, we will discuss how eicosanoids affect the functions of DCs and macrophages in the asthmatic lung and how this leads to aberrant T cell differentiation that causes disease.