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1.
Cells ; 9(8)2020 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-32707842

RESUMO

The ectonucleotidases CD39 and CD73 regulate immune responses by balancing extracellular ATP and adenosine in inflammation and are likely to be involved in the pathophysiology of COVID-19. Here, we analyzed CD39 and CD73 on different lymphocyte populations in a small cohort of COVID-19 patients and in healthy individuals. We describe a significantly lower level of expression of CD73 on cytotoxic lymphocyte populations, including CD8+ T, natural killer T (NKT), and natural killer (NK) cells, during COVID-19. Interestingly, the decrease of CD73 on CD8+ T cells and NKT cells correlated with serum ferritin levels. Furthermore, we observed distinct functional differences between the CD73+ and CD73- subsets of CD8+ T cells and NKT cells with regard to cytokine/toxin secretion. In COVID-19 patients, the majority of the CD73-CD8+ T cells were capable of secreting granzyme B, perforin, tumor necrosis factor (TNF-α) or interferon-gamma (IFN-γ). To conclude, in this first study of CD39 and CD73 expression of lymphocytes in COVID-19, we show that CD8+ T cells and NKT cells lacking CD73 possess a significantly higher cytotoxic effector functionality compared to their CD73+ counterparts. Future studies should investigate differences of cellular CD39 and CD73 expression in patients at different disease stages and their potential as prognostic markers or targets for immunomodulatory therapies.


Assuntos
5'-Nucleotidase/metabolismo , Apirase/metabolismo , Infecções por Coronavirus/imunologia , Células Matadoras Naturais/imunologia , Células T Matadoras Naturais/imunologia , Pneumonia Viral/imunologia , Linfócitos T Citotóxicos/imunologia , Adenosina/metabolismo , Adulto , Idoso , Betacoronavirus , Infecções por Coronavirus/enzimologia , Feminino , Proteínas Ligadas por GPI/metabolismo , Granzimas/metabolismo , Humanos , Inflamação/enzimologia , Inflamação/imunologia , Interferon gama/metabolismo , Masculino , Pessoa de Meia-Idade , Pandemias , Perforina/metabolismo , Pneumonia Viral/enzimologia , Transdução de Sinais/imunologia , Linfócitos T Citotóxicos/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
2.
Cytokine ; 133: 155151, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32544563

RESUMO

Patients with COVID-19 who require ICU admission might have the cytokine storm. It is a state of out-of-control release of a variety of inflammatory cytokines. The molecular mechanism of the cytokine storm has not been explored extensively yet. The attachment of SARS-CoV-2 spike glycoprotein with angiotensin-converting enzyme 2 (ACE2), as its cellular receptor, triggers complex molecular events that leads to hyperinflammation. Four molecular axes that may be involved in SARS-CoV-2 driven inflammatory cytokine overproduction are addressed in this work. The virus-mediated down-regulation of ACE2 causes a burst of inflammatory cytokine release through dysregulation of the renin-angiotensin-aldosterone system (ACE/angiotensin II/AT1R axis), attenuation of Mas receptor (ACE2/MasR axis), increased activation of [des-Arg9]-bradykinin (ACE2/bradykinin B1R/DABK axis), and activation of the complement system including C5a and C5b-9 components. The molecular clarification of these axes will elucidate an array of therapeutic strategies to confront the cytokine storm in order to prevent and treat COVID-19 associated acute respiratory distress syndrome.


Assuntos
Betacoronavirus/metabolismo , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/metabolismo , Citocinas/metabolismo , Inflamação/metabolismo , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/imunologia , Pneumonia Viral/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Betacoronavirus/patogenicidade , Bradicinina/metabolismo , Complemento C5a/imunologia , Complemento C5a/metabolismo , Complemento C5b/imunologia , Complemento C5b/metabolismo , Infecções por Coronavirus/enzimologia , Humanos , Inflamação/enzimologia , Inflamação/imunologia , Modelos Moleculares , Pandemias , Pneumonia Viral/enzimologia , Proteínas Proto-Oncogênicas/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Sistema Renina-Angiotensina/imunologia
3.
Adv Exp Med Biol ; 1221: 97-135, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32274708

RESUMO

The cell surface heparan sulfate proteoglycan Syndecan-1 acts as an important co-receptor for receptor tyrosine kinases and chemokine receptors, and as an adhesion receptor for structural glycoproteins of the extracellular matrix. It serves as a substrate for heparanase, an endo-ß-glucuronidase that degrades specific domains of heparan sulfate carbohydrate chains and thereby alters the functional status of the proteoglycan and of Syndecan-1-bound ligands. Syndecan-1 and heparanase show multiple levels of functional interactions, resulting in mutual regulation of their expression, processing, and activity. These interactions are of particular relevance in the context of inflammation and malignant disease. Studies in animal models have revealed a mechanistic role of Syndecan-1 and heparanase in the regulation of contact allergies, kidney inflammation, multiple sclerosis, inflammatory bowel disease, and inflammation-associated tumorigenesis. Moreover, functional interactions between Syndecan-1 and heparanase modulate virtually all steps of tumor progression as defined in the Hallmarks of Cancer. Due to their prognostic value in cancer, and their mechanistic involvement in tumor progression, Syndecan-1 and heparanase have emerged as important drug targets. Data in preclinical models and preclinical phase I/II studies have already yielded promising results that provide a translational perspective.


Assuntos
Glucuronidase , Inflamação , Neoplasias , Sindecana-1 , Animais , Heparitina Sulfato/metabolismo , Humanos , Inflamação/enzimologia , Inflamação/metabolismo , Neoplasias/enzimologia , Neoplasias/metabolismo
4.
Cardiovasc Diabetol ; 19(1): 33, 2020 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-32169071

RESUMO

The proprotein convertase subtilisin/kexin type 9 (PCSK9) acts via a canonical pathway to regulate circulating low-density lipoprotein-cholesterol (LDL-C) via degradation of the LDL receptor (LDLR) on the liver cell surface. Published research has shown that PCSK9 is involved in atherosclerosis via a variety of non-classical mechanisms that involve lysosomal, inflammatory, apoptotic, mitochondrial, and immune pathways. In this review paper, we summarized these additional mechanisms and described how anti-PCSK9 therapy exerts effects through these mechanisms. These additional pathways further illustrate the regulatory role of PCSK9 in atherosclerosis and offer an in-depth interpretation of how the PCSK9 inhibitor exerts effects on the treatment of atherosclerosis.


Assuntos
Aterosclerose/enzimologia , LDL-Colesterol/sangue , Diabetes Mellitus/enzimologia , Dislipidemias/enzimologia , Inflamação/enzimologia , Pró-Proteína Convertase 9/metabolismo , Animais , Anticorpos Monoclonais/uso terapêutico , Anticolesterolemiantes/uso terapêutico , Aterosclerose/sangue , Aterosclerose/tratamento farmacológico , Aterosclerose/patologia , Diabetes Mellitus/sangue , Diabetes Mellitus/patologia , Dislipidemias/sangue , Dislipidemias/tratamento farmacológico , Dislipidemias/patologia , Células Endoteliais/enzimologia , Células Endoteliais/patologia , Humanos , Inflamação/sangue , Inflamação/patologia , Macrófagos/enzimologia , Macrófagos/patologia , Placa Aterosclerótica , Pró-Proteína Convertase 9/antagonistas & inibidores , Inibidores de Serino Proteinase/uso terapêutico
5.
Biochemistry (Mosc) ; 85(Suppl 1): S177-S195, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32087059

RESUMO

Enzymes of the phospholipase superfamily are involved in lipid metabolism, as well as regulation of membrane composition, cell signaling, and inflammation. This review provides an insight into the structure, functional properties, and biotechnological application of phospholipase A2 and phospholipases in general.


Assuntos
Biotecnologia , Indústria Alimentícia , Inibidores de Fosfolipase A2/uso terapêutico , Fosfolipases A2/química , Fosfolipases A2/metabolismo , Animais , Membrana Celular/enzimologia , Expressão Gênica , Humanos , Inflamação/tratamento farmacológico , Inflamação/enzimologia , Isoenzimas , Metabolismo dos Lipídeos/fisiologia , Fosfolipases A2/classificação , Fosfolipases A2/genética , Estrutura Secundária de Proteína , Transdução de Sinais/fisiologia
6.
Oncology ; 98(3): 131-137, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31958792

RESUMO

Interleukin-6 (IL-6) is a member of the pro-inflammatory cytokine family, induces the expression of a variety of proteins responsible for acute inflammation, and plays an important role in the proliferation and differentiation of cells in humans. IL-6 signaling is mediated by building a complex of IL-6, the transmembrane IL-6 receptor (mIL-6R) or with soluble forms of IL-6R (sIL-6R), and the signal-transducing subunit molecule gp130. Therefore, three modes for IL-6 signaling may occur in which IL-6 is binding to mIL-6R (classic), to sIL-6R (trans-signaling), or is joined through IL-6R to gp130 on nearby located cells (trans-presentation). These pathways, and the fact that gp130 is ubiquitously expressed, lead to the pleiotropic functions of IL-6. The control of IL-6 signaling is regulated through the induction of suppressor molecules after activation of the IL-6 pathways as well as through the presence of sIL-6R and gp130 forms in the blood. Vice versa, an overproduction of IL-6 and dysregulation of the IL-6 signaling pathways can result in inflammatory and autoimmune disorders as well as cancer development suggesting that IL-6 plays a significant role in the human cytokine network. Several therapeutic agents have been evaluated for inhibiting the cytokine itself, the signaling via the IL-6 receptor, or target kinases (e.g., JAK/STAT) associated with the signaling pathways. Amongst others, tocilizumab (anti-IL-6R humanized antibody) has been approved for the treatment of rheumatoid arthritis, cytokine release syndrome, and idiopathic multicentric Castleman's disease (iMCD), whereas siltuximab (an IL-6 antagonist) received approval for iMCD only. Although not all IL-6-associated diseases respond to IL-6 blockade, a better understanding of the underlying mechanisms of the IL-6 pathways may, therefore, help to find the best treatment for IL-6-associated diseases in the near future.


Assuntos
Mediadores da Inflamação/metabolismo , Inflamação/metabolismo , Interleucina-6/metabolismo , Transdução de Sinais , Anti-Inflamatórios/uso terapêutico , Humanos , Inflamação/tratamento farmacológico , Inflamação/enzimologia , Mediadores da Inflamação/antagonistas & inibidores , Interleucina-6/antagonistas & inibidores , Inibidores de Janus Quinases/uso terapêutico , Janus Quinases/antagonistas & inibidores , Janus Quinases/metabolismo , Terapia de Alvo Molecular , Receptores de Interleucina-6/antagonistas & inibidores , Receptores de Interleucina-6/metabolismo , Fatores de Transcrição STAT/antagonistas & inibidores , Fatores de Transcrição STAT/metabolismo
7.
Arterioscler Thromb Vasc Biol ; 40(3): 570-582, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31996020

RESUMO

OBJECTIVE: Uric acid is supposed but not yet determined to be associated with atherosclerosis. Uric acid is released from damaged cells to form urate crystal, which is recognized by the immune system to produce IL (interleukin)-1. Danger signals and IL-1 have been shown to play an important role in atherosclerosis. We determined whether the physiological level of soluble uric acid promotes inflammation and develops atherosclerosis. Approach and Results: The secretion of IL-1ß from human peripheral blood mononuclear cells mediated by NLRP3 (NACHT, LRR, and PYD domain-containing protein 3) inflammasome was promoted by physiological levels in serum uric acid. This augmentation of inflammation was mediated by the regulation of the AMPK (AMP-activated protein kinase)-mTOR (mammalian target of rapamycin) mitochondrial reactive oxygen species and HIF-1α (hypoxia-inducible factor-1α) pathway. In both of uricase transgenic and xanthine oxidase inhibitor-treated mice, decreased levels of uric acid resulted in the activation of AMPK and attenuation of the development of atherosclerotic plaques. Further, acute uric acid reduction by the administration of benzbromarone in healthy humans for 2 weeks significantly decreased plasma IL-18-an inflammasome-dependent cytokine. CONCLUSIONS: The data indicate that the development of atherosclerosis and inflammation is promoted by uric acid in vivo. Moreover, the lowering of uric acid levels attenuated inflammation via the activation of the AMPK pathway. This study provides mechanistic evidence of uric acid-lowering therapies for atherosclerosis.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Aterosclerose/enzimologia , Inflamação/enzimologia , Leucócitos Mononucleares/enzimologia , Ácido Úrico/sangue , Adulto , Animais , Aterosclerose/sangue , Aterosclerose/patologia , Aterosclerose/prevenção & controle , Benzobromarona/administração & dosagem , Biomarcadores/sangue , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Feminino , Células HEK293 , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Inflamassomos/genética , Inflamassomos/metabolismo , Inflamação/sangue , Inflamação/patologia , Inflamação/prevenção & controle , Mediadores da Inflamação/sangue , Interleucina-18/sangue , Interleucina-1beta/sangue , Interleucina-1beta/genética , Leucócitos Mononucleares/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Pessoa de Meia-Idade , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína do Fator Nuclear 45/sangue , Placa Aterosclerótica , Espécies Reativas de Oxigênio/metabolismo , Receptores de LDL/deficiência , Receptores de LDL/genética , Urato Oxidase/genética , Urato Oxidase/metabolismo , Uricosúricos/administração & dosagem , Xantina Oxidase/antagonistas & inibidores , Xantina Oxidase/metabolismo , Adulto Jovem
8.
Mol Cell Biochem ; 464(1-2): 119-130, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31754972

RESUMO

Myeloperoxidase (MPO), an oxidant-producing enzyme, stored in azurophilic granules of neutrophils has been recently shown to influence red blood cell (RBC) deformability leading to abnormalities in blood microcirculation. Native MPO is a homodimer, consisting of two identical protomers (monomeric MPO) connected by a single disulfide bond but in inflammatory foci as a result of disulfide cleavage monomeric MPO (hemi-MPO) can also be produced. This study investigated if two MPO isoforms have distinct effects on biophysical properties of RBCs. We have found that hemi-MPO, as well as the dimeric form, bind to the glycophorins A/B and band 3 protein on RBC's plasma membrane, that lead to reduced cell resistance to osmotic and acidic hemolysis, reduction in cell elasticity, significant changes in cell volume, morphology, and the conductance of RBC plasma membrane ion channels. Furthermore, we have shown for the first time that both dimeric and hemi-MPO lead to phosphatidylserine (PS) exposure on the outer leaflet of RBC membrane. However, the effects of hemi-MPO on the structural and functional properties of RBCs were lower compared to those of dimeric MPO. These findings suggest that the ability of MPO protein to influence RBC's biophysical properties depends on its conformation (dimeric or monomeric isoform). It is intriguing to speculate that hemi-MPO appearance in blood during inflammation can serve as a regulatory mechanism addressed to reduce abnormalities on RBC response, induced by dimeric MPO.


Assuntos
Membrana Eritrocítica/enzimologia , Peroxidase/metabolismo , Multimerização Proteica , Membrana Eritrocítica/patologia , Células HL-60 , Humanos , Inflamação/enzimologia , Inflamação/patologia , Isoenzimas/metabolismo , Fosfatidilserinas/metabolismo
9.
Life Sci ; 241: 117157, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31837332

RESUMO

Mitogen-activated protein kinase (MAPK)§ cascades are crucial signaling pathways in the regulation of the host immune response to infection. MAPK phosphatase (MKP)-1, an archetypal member of the MKP family, plays a pivotal role in the down-regulation of p38 and JNK. Studies using cultured macrophages have demonstrated a pivotal role of MKP-1 in the restraint of the biosynthesis of both pro-inflammatory and anti-inflammatory cytokines as well as chemokines. Using MKP-1 knockout mice, several groups have not only confirmed the critical importance of MKP-1 in the regulation of the cytokine synthesis in vivo during the acute host response to bacterial infections, but also revealed novel functions of MKP-1 in maintaining bactericidal functions and host metabolic activities. RNA-seq analyses on livers of septic mice infected with E. coli have revealed that MKP-1 deficiency caused substantial perturbation in the expression of over 5000 genes, an impressive >20% of the entire murine genome. Among the genes whose expression are dramatically affected by MKP-1 deficiency are those encoding metabolic regulators and acute phase response proteins. These studies demonstrate that MKP-1 is an essential gate-keeper of the acute innate immune response, facilitating pathogen killing and regulating the metabolic response during pathogenic infection. In this review article, we will summarize the studies on the function of MKP-1 during acute innate immune response in the regulation of inflammation, metabolism, and acute phase response. We will also discuss the role of MKP-1 in the actions of numerous immunomodulatory agents.


Assuntos
Fosfatase 1 de Especificidade Dupla/imunologia , Imunidade Inata/imunologia , Inflamação/imunologia , Animais , Fosfatase 1 de Especificidade Dupla/metabolismo , Humanos , Inflamação/enzimologia
10.
Immunology ; 159(2): 142-155, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31630388

RESUMO

Inflammation is a part of the body's immune response for protection against pathogenic infections and other cellular damages; however, chronic inflammation is a major cause of various diseases. One key step in the inflammatory response is the activation of inflammasomes, intracellular protein complexes comprising pattern recognition receptors and other inflammatory molecules. The role of the NLRP3 inflammasome in inflammatory responses has been extensively investigated; however, the caspase-11 inflammasome has been recently identified and has been classified as a 'non-canonical' inflammasome, and emerging studies have highlighted its role in inflammatory responses. Because the ligands and the mechanisms for the activation of these two inflammasomes are different, studies to date have separately described their roles, although recent studies have reported the functional cooperation between these two inflammasomes during an inflammatory response. This review discusses the studies investigating the functional crosstalk between non-canonical caspase-11 and canonical NLRP3 inflammasomes in the context of inflammatory responses; moreover, it provides insight for the development of novel anti-inflammatory therapeutics to prevent and treat infectious and inflammatory diseases.


Assuntos
Caspases/metabolismo , Doenças Transmissíveis/enzimologia , Inflamassomos/metabolismo , Inflamação/enzimologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Animais , Caspases/imunologia , Doenças Transmissíveis/imunologia , Interações Hospedeiro-Patógeno , Humanos , Inflamassomos/imunologia , Inflamação/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Transdução de Sinais
11.
Acta Neuropathol Commun ; 7(1): 210, 2019 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-31843022

RESUMO

Activated Caspase-6 (Casp6) is associated with age-dependent cognitive impairment and Alzheimer disease (AD). Mice expressing human Caspase-6 in hippocampal CA1 neurons develop age-dependent cognitive deficits, neurodegeneration and neuroinflammation. This study assessed if methylene blue (MB), a phenothiazine that inhibits caspases, alters Caspase-6-induced neurodegeneration and cognitive impairment in mice. Aged cognitively impaired Casp6-overexpressing mice were treated with methylene blue in drinking water for 1 month. Methylene blue treatment did not alter Caspase-6 levels, assessed by RT-PCR, western blot and immunohistochemistry, but inhibited fluorescently-labelled Caspase-6 activity in acute brain slice intact neurons. Methylene blue treatment rescued Caspase-6-induced episodic and spatial memory deficits measured by novel object recognition and Barnes maze, respectively. Methylene blue improved synaptic function of hippocampal CA1 neurons since theta-burst long-term potentiation (LTP), measured by field excitatory postsynaptic potentials (fEPSPs) in acute brain slices, was successfully induced in the Schaffer collateral-CA1 pathway in methylene blue-treated, but not in vehicle-treated, Caspase-6 mice. Increased neuroinflammation, measured by ionized calcium binding adaptor molecule 1 (Iba1)-positive microglia numbers and subtypes, and glial fibrillary acidic protein (GFAP)-positive astrocytes, were decreased by methylene blue treatment. Therefore, methylene blue reverses Caspase-6-induced cognitive deficits by inhibiting Caspase-6, and Caspase-6-mediated neurodegeneration and neuroinflammation. Our results indicate that Caspase-6-mediated damage is reversible months after the onset of cognitive deficits and suggest that methylene blue could benefit Alzheimer disease patients by reversing Caspase-6-mediated cognitive decline.


Assuntos
Envelhecimento/metabolismo , Caspase 6/metabolismo , Inibidores de Caspase/uso terapêutico , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/enzimologia , Azul de Metileno/uso terapêutico , Envelhecimento/efeitos dos fármacos , Envelhecimento/patologia , Animais , Inibidores de Caspase/farmacologia , Disfunção Cognitiva/patologia , Feminino , Humanos , Inflamação/tratamento farmacológico , Inflamação/enzimologia , Inflamação/patologia , Masculino , Azul de Metileno/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos
12.
Exp Neurol ; 322: 113056, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31494101

RESUMO

Inflammatory response triggered by nerve injury plays important roles in the development of neurological disorders, such as neuropathic pain. The signaling events leading to inflammation in the nervous system remain poorly understood. Here, by deleting Dlk in sensory neurons driven by Wnt1a-Cre, we show that dual leucine zipper kinase (DLK) is required for the neuronal intrinsic immune response to induce cytokines and chemokines such as Ccl2, Ccl7, and Ccl12 upon nerve injury. The DLK-controlled injury response in sensory neurons could regulate CD11b+ immune cell infiltration in the dorsal root ganglia, as well as microgliosis and astrogliosis in the spinal dorsal horn but not the ventral horn. Deficiency of Dlk drastically alleviates the neuropathic pain elicited by chronic constriction injury of the sciatic nerve. Thus, DLK is an essential component that mediates the neuronal intrinsic immune response to nerve injury in sensory neurons and regulates inflammation in the spinal cord.


Assuntos
Inflamação/enzimologia , MAP Quinase Quinase Quinases/imunologia , Neuralgia/enzimologia , Neuralgia/imunologia , Células Receptoras Sensoriais/enzimologia , Animais , Inflamação/imunologia , Inflamação/patologia , MAP Quinase Quinase Quinases/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neuralgia/patologia , Neuroglia/patologia , Células Receptoras Sensoriais/imunologia , Células Receptoras Sensoriais/patologia
13.
Nat Commun ; 10(1): 4116, 2019 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-31511522

RESUMO

Damage-associated molecular patterns (DAMPs) are molecules that can be actively or passively released by injured tissues and that activate the immune system. Here we show that nicotinate phosphoribosyltransferase (NAPRT), detected by antibody-mediated assays and mass spectrometry, is an extracellular ligand for Toll-like receptor 4 (TLR4) and a critical mediator of inflammation, acting as a DAMP. Exposure of human and mouse macrophages to NAPRT activates the inflammasome and NF-κB for secretion of inflammatory cytokines. Furthermore, NAPRT enhances monocyte differentiation into macrophages by inducing macrophage colony-stimulating factor. These NAPRT-induced effects are independent of NAD-biosynthetic activity, but rely on NAPRT binding to TLR4. In line with our finding that NAPRT mediates endotoxin tolerance in vitro and in vivo, sera from patients with sepsis contain the highest levels of NAPRT, compared to patients with other chronic inflammatory conditions. Together, these data identify NAPRT as a endogenous ligand for TLR4 and a mediator of inflammation.


Assuntos
Espaço Extracelular/metabolismo , Inflamação/enzimologia , Pentosiltransferases/metabolismo , Receptor 4 Toll-Like/metabolismo , Diferenciação Celular , Líquido Extracelular/enzimologia , Humanos , Inflamação/genética , Inflamação/patologia , Fator Estimulador de Colônias de Macrófagos/metabolismo , Macrófagos/metabolismo , Monócitos/citologia , Células Mieloides/metabolismo , Nicotinamida Fosforribosiltransferase/química , Nicotinamida Fosforribosiltransferase/metabolismo , Pentosiltransferases/sangue , Pentosiltransferases/química , Ligação Proteica , Fatores de Risco , Sepse/sangue , Sepse/enzimologia
14.
Am J Physiol Heart Circ Physiol ; 317(5): H877-H890, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31441689

RESUMO

There is substantial evidence that chronic heart failure in humans and in animal models is associated with inflammation. Ischemic interventions such as myocardial infarction lead to necrotic cell death and release of damage associated molecular patterns, factors that signal cell damage and induce expression of proinflammatory chemokines and cytokines. It has recently become evident that nonischemic interventions are also associated with increases in inflammatory genes and immune cell accumulation in the heart and that these contribute to fibrosis and ventricular dysfunction. How proinflammatory responses are elicited in nonischemic heart disease which is not, at least initially, associated with cell death is a critical unanswered question. In this review we provide evidence supporting the hypothesis that cardiomyocytes are an initiating site of inflammatory gene expression in response to nonischemic stress. Furthermore we discuss the role of the multifunctional Ca2+/calmodulin-regulated kinase, CaMKIIδ, as a transducer of stress signals to nuclear factor-κB activation, expression of proinflammatory cytokines and chemokines, and priming and activation of the NOD-like pyrin domain-containing protein 3 (NLRP3) inflammasome in cardiomyocytes. We summarize recent evidence that subsequent macrophage recruitment, fibrosis and contractile dysfunction induced by angiotensin II infusion or transverse aortic constriction are ameliorated by blockade of CaMKII, of monocyte chemoattractant protein-1/C-C chemokine receptor type 2 signaling, or of NLRP3 inflammasome activation.


Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Cardiopatias/enzimologia , Inflamassomos/metabolismo , Mediadores da Inflamação/metabolismo , Inflamação/enzimologia , Miócitos Cardíacos/enzimologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Animais , Modelos Animais de Doenças , Fibrose , Cardiopatias/imunologia , Cardiopatias/patologia , Cardiopatias/fisiopatologia , Humanos , Inflamassomos/imunologia , Inflamação/imunologia , Inflamação/patologia , Inflamação/fisiopatologia , Mediadores da Inflamação/imunologia , Miócitos Cardíacos/imunologia , Miócitos Cardíacos/patologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Transdução de Sinais
15.
J Biol Chem ; 294(40): 14591-14602, 2019 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-31375561

RESUMO

Zika virus (ZIKV)3 is an enveloped, single-stranded, positive-sense RNA virus of the Flaviviridae family that has emerged as a public health threat because of its global transmission and link to microcephaly. Currently there is no vaccine for this virus. Conversion of cholesterol to 25-hydroxycholesterol by cholesterol 25-hydroxylase (CH25H) has been shown to have broad antiviral properties. However, the molecular basis of induction of CH25H in humans is not known. Elucidation of signaling and transcriptional events for induction of CH25H expression is critical for designing therapeutic antiviral agents. In this study, we show that CH25H is induced by ZIKV infection or Toll-like receptor stimulation. Interestingly, CH25H is induced by pro-inflammatory cytokines, including IL-1ß, tumor necrosis factor α, and IL-6, and this induction depends on the STAT1 transcription factor. Additionally, we observed that cAMP-dependent transcription factor (ATF3) weakly binds to the CH25H promoter, suggesting cooperation with STAT1. However, ZIKV-induced CH25H was independent of type I interferon. These findings provide important information for understanding how the Zika virus induces innate inflammatory responses and promotes the expression of anti-viral CH25H protein.


Assuntos
Fator 3 Ativador da Transcrição/genética , Fator de Transcrição STAT1/genética , Esteroide Hidroxilases/genética , Infecção por Zika virus/genética , Zika virus/genética , Antivirais/química , Antivirais/metabolismo , Citocinas/genética , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/genética , Regulação Enzimológica da Expressão Gênica , Humanos , Inflamação/enzimologia , Inflamação/genética , Inflamação/virologia , Interferon Tipo I/genética , Interleucina-1beta/genética , Interleucina-6/genética , Macrófagos/virologia , Esteroide Hidroxilases/química , Receptores Toll-Like/genética , Fator de Necrose Tumoral alfa/genética , Replicação Viral/genética , Zika virus/patogenicidade , Infecção por Zika virus/enzimologia , Infecção por Zika virus/virologia
16.
Int J Mol Sci ; 20(13)2019 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-31277498

RESUMO

The maintenance of physiological levels of nitric oxide (NO) produced by eNOS represents a key element for vascular endothelial homeostasis. On the other hand, NO overproduction, due to the activation of iNOS under different stress conditions, leads to endothelial dysfunction and, in the late stages, to the development of atherosclerosis. Oxidized LDLs (oxLDLs) represent the major candidates to trigger biomolecular processes accompanying endothelial dysfunction and vascular inflammation leading to atherosclerosis, though the pathophysiological mechanism still remains to be elucidated. Here, we summarize recent evidence suggesting that oxLDLs produce significant impairment in the modulation of the eNOS/iNOS machinery, downregulating eNOS via the HMGB1-TLR4-Caveolin-1 pathway. On the other hand, increased oxLDLs lead to sustained activation of the scavenger receptor LOX-1 and, subsequently, to NFkB activation, which, in turn, increases iNOS, leading to EC oxidative stress. Finally, these events are associated with reduced protective autophagic response and accelerated apoptotic EC death, which activates atherosclerotic development. Taken together, this information sheds new light on the pathophysiological mechanisms of oxLDL-related impairment of EC functionality and opens new perspectives in atherothrombosis prevention.


Assuntos
Aterosclerose/enzimologia , Endotélio Vascular/enzimologia , Endotélio Vascular/patologia , Inflamação/enzimologia , Lipoproteínas LDL/metabolismo , Óxido Nítrico Sintase/metabolismo , Animais , Humanos , Inflamação/patologia , Óxido Nítrico/metabolismo
17.
EMBO Mol Med ; 11(8): e9903, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31265218

RESUMO

Malaria is a highly inflammatory disease caused by Plasmodium infection of host erythrocytes. However, the parasite does not induce inflammatory cytokine responses in macrophages in vitro and the source of inflammation in patients remains unclear. Here, we identify oxidative stress, which is common in malaria, as an effective trigger of the inflammatory activation of macrophages. We observed that extracellular reactive oxygen species (ROS) produced by xanthine oxidase (XO), an enzyme upregulated during malaria, induce a strong inflammatory cytokine response in primary human monocyte-derived macrophages. In malaria patients, elevated plasma XO activity correlates with high levels of inflammatory cytokines and with the development of cerebral malaria. We found that incubation of macrophages with plasma from these patients can induce a XO-dependent inflammatory cytokine response, identifying a host factor as a trigger for inflammation in malaria. XO-produced ROS also increase the synthesis of pro-IL-1ß, while the parasite activates caspase-1, providing the two necessary signals for the activation of the NLRP3 inflammasome. We propose that XO-produced ROS are a key factor for the trigger of inflammation during malaria.


Assuntos
Inflamação/enzimologia , Macrófagos/enzimologia , Malária Cerebral/enzimologia , Malária Falciparum/enzimologia , Estresse Oxidativo , Plasmodium falciparum/patogenicidade , Espécies Reativas de Oxigênio/metabolismo , Xantina Oxidase/metabolismo , Caspase 1/metabolismo , Células Cultivadas , Citocinas/metabolismo , Interações Hospedeiro-Patógeno , Humanos , Inflamação/sangue , Inflamação/parasitologia , Mediadores da Inflamação/metabolismo , Ativação de Macrófagos , Macrófagos/parasitologia , Malária Cerebral/sangue , Malária Cerebral/parasitologia , Malária Falciparum/sangue , Malária Falciparum/parasitologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Transdução de Sinais
18.
Medicine (Baltimore) ; 98(28): e16429, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31305465

RESUMO

Significant liver histological changes (SLHC) were defined as moderate to severe liver inflammation (A2 or higher) and/or fibrosis (F2 or higher) using the METAVIR scoring system. This study aimed to develop an algorithm for the non-invasive detection of SLHC in patients with chronic hepatitis B (CHB) and normal or mildly elevated alanine transaminase (ALT) levels.Using liver histology as gold standard, we developed a simple algorithm for the diagnosis of SLHC in a training set (504 patients), and then validated the diagnostic accuracy in a validation set (166 patients).A new algorithm (AAG) attributed to age, ALT, and gamma-glutamyl transpeptidase (GGT) was developed. In the training set, the area under ROC curve (AUROC) of AAG was significantly higher than that of ALT, aspartate transaminase (AST), GPR, and APRI for the diagnosis of SLHC (0.74, 0.68, 0.65, 0.56, and 0.53, respectively; all P < .05). In the validation set, the AUROC of AAG was also higher than that of ALT, AST, GPR, and APRI (0.73, 0.65, 0.62, 0.62, and 0.61, respectively; all P < .05). Using AAG ≥ 2, the sensitivity and negative predictive value was 84% to 98% and 75% to 94%, respectively, for the diagnosis of SLHC. Using AAG ≥ 6, the specificity and positive predictive value was 93% to 97% and 67% to 79%, respectively, for the diagnosis of SLHC.The AAG algorithm represents a novel noninvasive method for the diagnosis of SLHC in CHB patients with normal or mildly elevated ALT levels.


Assuntos
Alanina Transaminase/sangue , Algoritmos , Hepatite B Crônica/diagnóstico , Inflamação/diagnóstico , Cirrose Hepática/diagnóstico , Adulto , Biomarcadores/sangue , Biópsia , Feminino , Hepatite B Crônica/enzimologia , Humanos , Inflamação/enzimologia , Fígado/patologia , Cirrose Hepática/enzimologia , Masculino , Estudos Retrospectivos , Sensibilidade e Especificidade
19.
Microbes Infect ; 21(10): 423-431, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31207286

RESUMO

Protein ADP-ribosylation is a reversible post-translational modification, which alters protein activity, localization, interactome or stability, leading to perturbation of cell signaling. This review summarizes the emerging data indicating that host cell ADP-ribosylating enzymes, poly(ADP-ribose) polymerases (PARPs), influence the course of a bacterial infection, in parallel to ADP-ribosylating bacterial toxins. Host cell PARP targeting could be an efficient therapeutic approach to treat certain bacterial infections, possibly by repurposing the approved or clinical trial PARP inhibitors developed for cancer therapy.


Assuntos
Bactérias/metabolismo , Infecções Bacterianas/enzimologia , Infecções Bacterianas/imunologia , Poli(ADP-Ribose) Polimerases/imunologia , ADP-Ribosilação/efeitos dos fármacos , Animais , Bactérias/classificação , Infecções Bacterianas/tratamento farmacológico , Infecções Bacterianas/metabolismo , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interações Hospedeiro-Patógeno/imunologia , Humanos , Inflamação/tratamento farmacológico , Inflamação/enzimologia , Inflamação/imunologia , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Poli(ADP-Ribose) Polimerases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia
20.
Arterioscler Thromb Vasc Biol ; 39(6): 1182-1190, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31070471

RESUMO

Objective- Inflammation is a causal risk factor for cardiovascular disease (CVD). sPLA2-IIA (group IIA secretory phospholipase A2) plays an integral role in regulating vascular inflammation. Although studies investigated sPLA2-IIA in secondary prevention, we prospectively evaluated sPLA2-IIA mass and genetic variants with CVD events in a primary prevention population with chronic inflammation. Approach and Results- The JUPITER trial (Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin) randomized participants with LDL (low-density lipoprotein) <130 mg/dL and hsCRP (high-sensitivity C-reactive protein) ≥2 mg/L to high-intensity rosuvastatin versus placebo. Baseline and 1-year plasma sPLA2-IIA mass was measured (N=11 269 baseline; N=9620 1 year). We also identified genetic variants influencing sPLA2-IIA using genome-wide association and examined them with CVD. Three hundred thirteen incident CVD events occurred during follow-up. Baseline sPLA2-IIA mass (median, 25th-75th percentile: 3.81, 2.49-6.03 ng/mL) was associated with increased risk of CVD: risk factor-adjusted hazard ratio (95% CI; P) per SD increment: 1.22 (1.08-1.38; P=0.002). This remained significant (1.18; 1.04-1.35; P=0.01) after incrementally adjusting for hsCRP. Similar estimates were observed in rosuvastatin and placebo groups ( P treatment interaction>0.05). The rs11573156C variant in PLA2G2A (encoding sPLA2-IIA) had the strongest effect on sPLA2-II: median (25th-75th percentile, ng/mL) for CC and GG genotypes: 2.79 (1.97-4.01) and 7.38 (5.38-10.19), respectively; and had nonsignificant trend for higher CVD risk (hazard ratio, 1.11; 95% CI, 0.89-1.38; P=0.34). Conclusions- In the JUPITER population recruited on chronic inflammation, sPLA2-IIA mass was associated with CVD risk relating to vascular inflammation not fully reflected by hsCRP. Additional studies, including larger functional genetic and clinical studies, are needed to determine whether sPLA2-IIA may be a potential pharmacological target for primary prevention of CVD. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT00239681.


Assuntos
Doenças Cardiovasculares/enzimologia , Dislipidemias/enzimologia , Fosfolipases A2 do Grupo II/sangue , Inflamação/enzimologia , Idoso , Anti-Inflamatórios/uso terapêutico , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/prevenção & controle , Método Duplo-Cego , Dislipidemias/tratamento farmacológico , Dislipidemias/epidemiologia , Dislipidemias/genética , Feminino , Predisposição Genética para Doença , Fosfolipases A2 do Grupo II/genética , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Incidência , Inflamação/tratamento farmacológico , Inflamação/epidemiologia , Inflamação/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Prevenção Primária , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Rosuvastatina Cálcica/uso terapêutico , Fatores de Tempo , Resultado do Tratamento
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