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1.
Biomolecules ; 11(7)2021 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-34356636

RESUMO

Sepsis is a life-threatening medical condition that occurs when the host has an uncontrolled or abnormal immune response to overwhelming infection. It is now widely accepted that sepsis occurs in two concurrent phases, which consist of an initial immune activation phase followed by a chronic immunosuppressive phase, leading to immune cell death. Depending on the severity of the disease and the pathogen involved, the hosts immune system may not fully recover, leading to ongoing complications proceeding the initial infection. As such, sepsis remains one of the leading causes of morbidity and mortality world-wide, with treatment options limited to general treatment in intensive care units (ICU). Lack of specific treatments available for sepsis is mostly due to our limited knowledge of the immuno-physiology associated with the disease. This review will provide a comprehensive overview of the mechanisms and cell types involved in eliciting infection-induced immune activation from both the innate and adaptive immune system during sepsis. In addition, the mechanisms leading to immune cell death following hyperactivation of immune cells will be explored. The evaluation and better understanding of the cellular and systemic responses leading to disease onset could eventuate into the development of much needed therapies to combat this unrelenting disease.


Assuntos
Imunidade Adaptativa , Imunidade Inata , Sepse/imunologia , Animais , Morte Celular/imunologia , Humanos , Sepse/patologia , Sepse/terapia
2.
J Clin Invest ; 131(20)2021 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-34464357

RESUMO

BACKGROUNDMultisystem inflammatory syndrome in children (MIS-C) is a rare but potentially severe illness that follows exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Kawasaki disease (KD) shares several clinical features with MIS-C, which prompted the use of intravenous immunoglobulin (IVIG), a mainstay therapy for KD. Both diseases share a robust activation of the innate immune system, including the IL-1 signaling pathway, and IL-1 blockade has been used for the treatment of both MIS-C and KD. The mechanism of action of IVIG in these 2 diseases and the cellular source of IL-1ß have not been defined.METHODSThe effects of IVIG on peripheral blood leukocyte populations from patients with MIS-C and KD were examined using flow cytometry and mass cytometry (CyTOF) and live-cell imaging.RESULTSCirculating neutrophils were highly activated in patients with KD and MIS-C and were a major source of IL-1ß. Following IVIG treatment, activated IL-1ß+ neutrophils were reduced in the circulation. In vitro, IVIG was a potent activator of neutrophil cell death via PI3K and NADPH oxidase, but independently of caspase activation.CONCLUSIONSActivated neutrophils expressing IL-1ß can be targeted by IVIG, supporting its use in both KD and MIS-C to ameliorate inflammation.FUNDINGPatient Centered Outcomes Research Institute; NIH; American Asthma Foundation; American Heart Association; Novo Nordisk Foundation; NIGMS; American Academy of Allergy, Asthma and Immunology Foundation.


Assuntos
COVID-19/complicações , Imunoglobulinas Intravenosas/uso terapêutico , Síndrome de Linfonodos Mucocutâneos/imunologia , Síndrome de Linfonodos Mucocutâneos/terapia , Síndrome de Resposta Inflamatória Sistêmica/imunologia , Síndrome de Resposta Inflamatória Sistêmica/terapia , COVID-19/sangue , COVID-19/imunologia , COVID-19/terapia , Estudos de Casos e Controles , Morte Celular/imunologia , Linhagem da Célula/imunologia , Criança , Pré-Escolar , Proteína Ligante Fas/imunologia , Feminino , Humanos , Lactente , Interleucina-1beta/antagonistas & inibidores , Interleucina-1beta/sangue , Contagem de Leucócitos , Masculino , Síndrome de Linfonodos Mucocutâneos/sangue , Ativação de Neutrófilo , Neutrófilos/classificação , Neutrófilos/imunologia , Neutrófilos/patologia , Síndrome de Resposta Inflamatória Sistêmica/sangue
3.
J Biol Chem ; 297(4): 101098, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34418431

RESUMO

The progressive loss of CD4+ T cells during HIV infection of lymphoid tissues involves both the apoptotic death of activated and productively infected CD4 T cells and the pyroptotic death of large numbers of resting and abortively infected bystander CD4 T cells. HIV spreads both through cellular release of virions and cell-to-cell transmission involving the formation of virological synapses. Cell-to-cell transmission results in high-level transfer of large quantities of virions to the target cell exceeding that achieved with cell-free virions. Broadly neutralizing anti-HIV antibodies (bNAbs) binding to HIV envelope protein capably block cell-free virus spread, and when added at higher concentrations can also interdict cell-to-cell transmission. Exploiting these distinct dose-response differences, we now show that four different bNAbs block the pyroptotic death of bystander cells, but only when added at concentrations sufficient to block cell-to-cell transmission. These findings further support the conclusion that HIV killing of abortively infected bystander CD4 T cells requires cell-to-cell transfer of virions. As bNAbs attract more interest as potential therapeutics, it will be important to consider the higher concentrations of these antibodies required to block the inflammatory death of bystander CD4 T cells.


Assuntos
Anticorpos Neutralizantes/imunologia , Efeito Espectador/imunologia , Linfócitos T CD4-Positivos/imunologia , Anticorpos Anti-HIV/imunologia , Infecções por HIV , HIV-1/imunologia , Morte Celular/imunologia , Infecções por HIV/imunologia , Infecções por HIV/prevenção & controle , Infecções por HIV/transmissão , Humanos
5.
J Clin Invest ; 131(13)2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34196308

RESUMO

Clinical immunotherapy approaches are lacking efficacy in the treatment of glioblastoma (GBM). In this study, we sought to reverse local and systemic GBM-induced immunosuppression using the Helicobacter pylori neutrophil-activating protein (NAP), a potent TLR2 agonist, as an immunostimulatory transgene expressed in an oncolytic measles virus (MV) platform, retargeted to allow viral entry through the urokinase-type plasminogen activator receptor (uPAR). While single-agent murine anti-PD1 treatment or repeat in situ immunization with MV-s-NAP-uPA provided modest survival benefit in MV-resistant syngeneic GBM models, the combination treatment led to synergy with a cure rate of 80% in mice bearing intracranial GL261 tumors and 72% in mice with CT-2A tumors. Combination NAP-immunovirotherapy induced massive influx of lymphoid cells in mouse brain, with CD8+ T cell predominance; therapeutic efficacy was CD8+ T cell dependent. Inhibition of the IFN response pathway using the JAK1/JAK2 inhibitor ruxolitinib decreased PD-L1 expression on myeloid-derived suppressor cells in the brain and further potentiated the therapeutic effect of MV-s-NAP-uPA and anti-PD1. Our findings support the notion that MV strains armed with bacterial immunostimulatory antigens represent an effective strategy to overcome the limited efficacy of immune checkpoint inhibitor-based therapies in GBM, creating a promising translational strategy for this lethal brain tumor.


Assuntos
Antígenos de Bactérias/uso terapêutico , Neoplasias Encefálicas/terapia , Glioblastoma/terapia , Terapia Viral Oncolítica/métodos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Animais , Antígenos de Bactérias/administração & dosagem , Antígenos de Bactérias/genética , Proteínas de Bactérias/genética , Proteínas de Bactérias/imunologia , Proteínas de Bactérias/uso terapêutico , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/patologia , Linfócitos T CD8-Positivos/imunologia , Morte Celular/imunologia , Linhagem Celular Tumoral , Terapia Combinada , Citocinas/metabolismo , Efeito Citopatogênico Viral , Feminino , Glioblastoma/imunologia , Glioblastoma/patologia , Humanos , Linfócitos do Interstício Tumoral/imunologia , Vírus do Sarampo/genética , Vírus do Sarampo/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Nus , Vírus Oncolíticos/genética , Vírus Oncolíticos/imunologia , Receptores de Ativador de Plasminogênio Tipo Uroquinase/imunologia , Pesquisa Médica Translacional , Internalização do Vírus
6.
Clin Transl Sci ; 14(6): 2348-2359, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34121337

RESUMO

Coronavirus disease 2019 (COVID-19) global pandemic is caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) viral infection, which can lead to pneumonia, lung injury, and death in susceptible populations. Understanding viral dynamics of SARS-CoV-2 is critical for development of effective treatments. An Immune-Viral Dynamics Model (IVDM) is developed to describe SARS-CoV-2 viral dynamics and COVID-19 disease progression. A dataset of 60 individual patients with COVID-19 with clinical viral load (VL) and reported disease severity were assembled from literature. Viral infection and replication mechanisms of SARS-CoV-2, viral-induced cell death, and time-dependent immune response are incorporated in the model to describe the dynamics of viruses and immune response. Disease severity are tested as a covariate to model parameters. The IVDM was fitted to the data and parameters were estimated using the nonlinear mixed-effect model. The model can adequately describe individual viral dynamics profiles, with disease severity identified as a covariate on infected cell death rate. The modeling suggested that it takes about 32.6 days to reach 50% of maximum cell-based immunity. Simulations based on virtual populations suggested a typical mild case reaches VL limit of detection (LOD) by 13 days with no treatment, a moderate case by 17 days, and a severe case by 41 days. Simulations were used to explore hypothetical treatments with different initiation time, disease severity, and drug effects to demonstrate the usefulness of such modeling in informing decisions. Overall, the IVDM modeling and simulation platform enables simulations for viral dynamics and treatment efficacy and can be used to aid in clinical pharmacokinetic/pharmacodynamic (PK/PD) and dose-efficacy response analysis for COVID-19 drug development.


Assuntos
Antivirais/farmacologia , COVID-19/tratamento farmacológico , Desenvolvimento de Medicamentos/métodos , Interações entre Hospedeiro e Microrganismos/imunologia , Modelos Biológicos , Antivirais/uso terapêutico , COVID-19/diagnóstico , COVID-19/imunologia , COVID-19/virologia , Morte Celular/efeitos dos fármacos , Morte Celular/imunologia , Conjuntos de Dados como Assunto , Relação Dose-Resposta a Droga , Interações entre Hospedeiro e Microrganismos/efeitos dos fármacos , Humanos , Dinâmica não Linear , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/imunologia , Índice de Gravidade de Doença , Resultado do Tratamento , Carga Viral
7.
Cell Death Dis ; 12(5): 447, 2021 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-33953171

RESUMO

Ischaemic stroke is becoming the most common cerebral disease in aging populations, but the underlying molecular mechanism of the disease has not yet been fully elucidated. Increasing evidence has indicated that an excess of iron contributes to brain damage in cerebral ischaemia/reperfusion (I/R) injury. Although mitochondrial ferritin (FtMt) plays a critical role in iron homeostasis, the molecular function of FtMt in I/R remains unknown. We herein report that FtMt levels are upregulated in the ischaemic brains of mice. Mice lacking FtMt experience more severe brain damage and neurological deficits, accompanied by typical molecular features of ferroptosis, including increased lipid peroxidation and disturbed glutathione (GSH) after cerebral I/R. Conversely, FtMt overexpression reverses these changes. Further investigation shows that Ftmt ablation promotes I/R-induced inflammation and hepcidin-mediated decreases in ferroportin1, thus markedly increasing total and chelatable iron. The elevated iron consequently facilitates ferroptosis in the brain of I/R. In brief, our results provide evidence that FtMt plays a critical role in protecting against cerebral I/R-induced ferroptosis and subsequent brain damage, thus providing a new potential target for the treatment/prevention of ischaemic stroke.


Assuntos
Morte Celular/imunologia , Ferritinas/metabolismo , Ferroptose/imunologia , Mitocôndrias/imunologia , Traumatismo por Reperfusão/imunologia , Animais , Humanos , Camundongos , Camundongos Knockout
8.
Nat Commun ; 12(1): 2451, 2021 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-33907187

RESUMO

Many pathogens infect hosts through specific organs, such as Ustilaginoidea virens, which infects rice panicles. Here, we show that a microbe-associated molecular pattern (MAMP), Ser-Thr-rich Glycosyl-phosphatidyl-inositol-anchored protein (SGP1) from U. virens, induces immune responses in rice leaves but not panicles. SGP1 is widely distributed among fungi and acts as a proteinaceous, thermostable elicitor of BAK1-dependent defense responses in N. benthamiana. Plants specifically recognize a 22 amino acid peptide (SGP1 N terminus peptide 22, SNP22) in its N-terminus that induces cell death, oxidative burst, and defense-related gene expression. Exposure to SNP22 enhances rice immunity signaling and resistance to infection by multiple fungal and bacterial pathogens. Interestingly, while SGP1 can activate immune responses in leaves, SGP1 is required for U. virens infection of rice panicles in vivo, showing it contributes to the virulence of a panicle adapted pathogen.


Assuntos
Proteínas Fúngicas/imunologia , Hypocreales/patogenicidade , Oryza/imunologia , Doenças das Plantas/imunologia , Folhas de Planta/imunologia , Proteínas de Plantas/imunologia , Sequência de Aminoácidos , Morte Celular/genética , Morte Celular/imunologia , Proteínas Fúngicas/genética , Regulação da Expressão Gênica , Glicosilfosfatidilinositóis/química , Glicosilfosfatidilinositóis/metabolismo , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Hypocreales/genética , Hypocreales/crescimento & desenvolvimento , Hypocreales/imunologia , Inflorescência/genética , Inflorescência/imunologia , Inflorescência/microbiologia , Oryza/genética , Oryza/microbiologia , Padrões Moleculares Associados a Patógenos/imunologia , Padrões Moleculares Associados a Patógenos/metabolismo , Peptídeos/genética , Peptídeos/imunologia , Células Vegetais/imunologia , Células Vegetais/patologia , Doenças das Plantas/genética , Doenças das Plantas/microbiologia , Imunidade Vegetal/genética , Folhas de Planta/genética , Folhas de Planta/microbiologia , Proteínas de Plantas/genética , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Transdução de Sinais , Virulência
9.
Biomolecules ; 11(5)2021 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-33924766

RESUMO

Chronic inflammatory disorders are characterised by aberrant and exaggerated inflammatory immune cell responses. Modes of extrinsic cell death, apoptosis and necroptosis, have now been shown to be potent drivers of deleterious inflammation, and mutations in core repressors of these pathways underlie many autoinflammatory disorders. The receptor-interacting protein (RIP) kinases, RIPK1 and RIPK3, are integral players in extrinsic cell death signalling by regulating the production of pro-inflammatory cytokines, such as tumour necrosis factor (TNF), and coordinating the activation of the NOD-like receptor protein 3 (NLRP3) inflammasome, which underpin pathological inflammation in numerous chronic inflammatory disorders. In this review, we firstly give an overview of the inflammatory cell death pathways regulated by RIPK1 and RIPK3. We then discuss how dysregulated signalling along these pathways can contribute to chronic inflammatory disorders of the joints, skin, and gastrointestinal tract, and discuss the emerging evidence for targeting these RIP kinases in the clinic.


Assuntos
Inflamação/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Animais , Apoptose/fisiologia , Morte Celular/imunologia , Doença Crônica , Citocinas/metabolismo , Humanos , Inflamassomos/metabolismo , Inflamação/fisiopatologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Necrose/metabolismo , Fosforilação , Proteínas Quinases/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/fisiologia , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismo
10.
Int J Mol Sci ; 22(4)2021 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-33671651

RESUMO

By dint of the aging population and further deepened with the Covid-19 pandemic, lung disease has turned out to be a major cause of worldwide morbidity and mortality. The condition is exacerbated when the immune system further attacks the healthy, rather than the diseased, tissue within the lung. Governed by unremittingly proliferating mesenchymal cells and increased collagen deposition, if inflammation persists, as frequently occurs in aging lungs, the tissue develops tumors and/or turns into scars (fibrosis), with limited regenerative capacity and organ failure. Fas ligand (FasL, a ligand of the Fas cell death receptor) is a key factor in the regulation of these processes. FasL is primarily found in two forms: full length (membrane, or mFasL) and cleaved (soluble, or sFasL). We and others found that T-cells expressing the mFasL retain autoimmune surveillance that controls mesenchymal, as well as tumor cell accumulation following an inflammatory response. However, mesenchymal cells from fibrotic lungs, tumor cells, or cells from immune-privileged sites, resist FasL+ T-cell-induced cell death. The mechanisms involved are a counterattack of immune cells by FasL, by releasing a soluble form of FasL that competes with the membrane version, and inhibits their cell death, promoting cell survival. This review focuses on understanding the previously unrecognized role of FasL, and in particular its soluble form, sFasL, in the serum of aged subjects, and its association with the evolution of lung disease, paving the way to new methods of diagnosis and treatment.


Assuntos
COVID-19/imunologia , Proteína Ligante Fas/imunologia , Pneumopatias/imunologia , Pulmão/imunologia , Fatores Etários , Idoso , COVID-19/sangue , Morte Celular/imunologia , Proteína Ligante Fas/sangue , Humanos , Imunidade , Pneumopatias/sangue , SARS-CoV-2/imunologia , SARS-CoV-2/isolamento & purificação , Linfócitos T/imunologia
11.
Methods Mol Biol ; 2265: 111-118, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33704709

RESUMO

Within the adaptive and innate immune system, effector lymphocytes known as cytotoxic T cells (CTLs) or natural killer (NK) cells play an essential role in host defense against tumor cells and virally infected cells. Here we describe a flow cytometry-based method to quantify CTLs or NK cell cytotoxic activity against melanoma cells. In this assay, spleen cells, peripheral blood mononuclear cells (PBMCs), or purified NK cell preparations are co-incubated at different ratios with a target tumor cell line. The target cells are pre-labeled with a fluorescent dye to allow their discrimination from the effector cells. After the incubation period, killed target cells are identified by a nucleic acid stain, which specifically permeates dead cells. This method is amenable to both diagnostic and research applications.


Assuntos
Testes Imunológicos de Citotoxicidade/métodos , Citometria de Fluxo/métodos , Células Matadoras Naturais/imunologia , Melanoma Experimental/imunologia , Linfócitos T Citotóxicos/imunologia , Animais , Técnicas de Cultura de Células/métodos , Morte Celular/imunologia , Linhagem Celular Tumoral , Técnicas de Cocultura/métodos , Feminino , Corantes Fluorescentes , Humanos , Leucócitos Mononucleares/imunologia , Camundongos , Baço/citologia , Baço/imunologia
12.
Front Immunol ; 12: 630430, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33679775

RESUMO

C-reactive protein (CRP) is the best-known acute phase protein. In humans, almost every type of inflammation is accompanied by an increase of CRP concentration. Until recently, the only known physiological function of CRP was the marking of cells to initiate their phagocytosis. This triggers the classical complement pathway up to C4, which helps to eliminate pathogens and dead cells. However, vital cells with reduced energy supply are also marked, which is useful in the case of a classical external wound because an important substrate for pathogens is disposed of, but is counterproductive at internal wounds (e.g., heart attack or stroke). This mechanism negatively affects clinical outcomes since it is established that CRP levels correlate with the prognosis of these indications. Here, we summarize what we can learn from a clinical study in which CRP was adsorbed from the bloodstream by CRP-apheresis. Recently, it was shown that CRP can have a direct effect on blood pressure in rabbits. This is interesting in regard to patients with high inflammation, as they often become tachycardic and need catecholamines. These two physiological effects of CRP apparently also occur in COVID-19. Parts of the lung become ischemic due to intra-alveolar edema and hemorrhage and in parallel CRP increases dramatically, hence it is assumed that CRP is also involved in this ischemic condition. It is meanwhile considered that most of the damage in COVID-19 is caused by the immune system. The high amounts of CRP could have an additional influence on blood pressure in severe COVID-19.


Assuntos
Proteína C-Reativa/imunologia , COVID-19/imunologia , Infarto do Miocárdio/imunologia , SARS-CoV-2/imunologia , Acidente Vascular Cerebral/imunologia , Animais , Morte Celular/imunologia , Hipóxia Celular/imunologia , Complemento C4/imunologia , Humanos , Coelhos
13.
J Immunol Methods ; 493: 113020, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33705736

RESUMO

Interfering with signalling pathways by targeting cell surface proteins has become an important strategy in the development of novel therapeutic agents. Notably, interfering with cytokine signalling revolutionised the treatment of chronic diseases. Cytokines can induce a range of effects that are not always accounted for in assays detecting cytokine binding to cell surface receptors and/or proximal signalling interference. Hence, robust assays are needed to characterise the activity of potential drug candidates targeting such effects. We chose interleukin-7 (IL7) as a cytokine model due to its long-term effect on T-cells. In this report we describe the development and refinement of an in vitro assay for measuring the long-term effect of IL7, more specifically on CD4+ T-cells, while the assay could be adapted to look at CD8+ T-cells. PBMCs and/or purified CD4+ T-cells stained with VPD450 (cell cycle dye) were expanded for 5 days using the mitogen Phytohemagglutinin and/or CD3/CD28 agonists. This resulted in cell proliferation (VPD450 dilution) and activation-induced cell death (7-AAD uptake) which was rescued by the addition of IL7, resulting in cell survival over a further 5 days. JAK-inhibitor (Tofactinib) or a blocking anti-IL7Rα antibody (clone R34.34) abolished cell survival suggesting antagonism, while another antibody (clone A019D5) displayed an agonist effect. These results were confirmed at the proximal signalling level using an IL7/STAT5-luciferase reporter assay. This novel assay for a biological long term effect may be useful for the characterisation of potential therapeutic drugs targeting the IL7/IL7R in CD4+ T-cells.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Interleucina-7/imunologia , Morte Celular/imunologia , Linhagem Celular , Humanos , Transdução de Sinais/imunologia
14.
Immunology ; 163(4): 399-415, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33682112

RESUMO

Regulated or programmed cell death plays a critical role in the development and tissue organization and function. In addition, it is intrinsically connected with immunity and host defence. An increasing cellular and molecular findings cause a change in the concept of cell death, revealing an expanding network of regulated cell death modalities and their biochemical programmes. Likewise, recent evidences demonstrate the interconnection between cell death pathways and how they are involved in different immune mechanisms. This work provides an overview of the main cell death programmes and their implication in innate immunity not only as an immunogenic/inflammatory process, but also as an active defence strategy during immune response and at the same time as a regulatory mechanism.


Assuntos
Morte Celular/imunologia , Inflamação/imunologia , Animais , Humanos , Imunidade Inata , Necrose
15.
Front Immunol ; 12: 631821, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33746968

RESUMO

Neutrophils or polymorphonuclear leukocytes (PMN) are key participants in the innate immune response for their ability to execute different effector functions. These cells express a vast array of membrane receptors that allow them to recognize and eliminate infectious agents effectively and respond appropriately to microenvironmental stimuli that regulate neutrophil functions, such as activation, migration, generation of reactive oxygen species, formation of neutrophil extracellular traps, and mediator secretion, among others. Currently, it has been realized that activated neutrophils can accomplish their effector functions and simultaneously activate mechanisms of cell death in response to different intracellular or extracellular factors. Although several studies have revealed similarities between the mechanisms of cell death of neutrophils and other cell types, neutrophils have distinctive properties, such as a high production of reactive oxygen species (ROS) and nitrogen species (RNS), that are important for their effector function in infections and pathologies such as cancer, autoimmune diseases, and immunodeficiencies, influencing their cell death mechanisms. The present work offers a synthesis of the conditions and molecules implicated in the regulation and activation of the processes of neutrophil death: apoptosis, autophagy, pyroptosis, necroptosis, NETosis, and necrosis. This information allows to understand the duality encountered by PMNs upon activation. The effector functions are carried out to eliminate invading pathogens, but in several instances, these functions involve activation of signaling cascades that culminate in the death of the neutrophil. This process guarantees the correct elimination of pathogenic agents, damaged or senescent cells, and the timely resolution of the inflammation that is essential for the maintenance of homeostasis in the organism. In addition, they alert the organism when the immunological system is being deregulated, promoting the activation of other cells of the immune system, such as B and T lymphocytes, which produce cytokines that potentiate the microbicide functions.


Assuntos
Morte Celular/imunologia , Neutrófilos/patologia , Apoptose/imunologia , Proteínas Reguladoras de Apoptose/metabolismo , Autofagia/imunologia , Armadilhas Extracelulares/imunologia , Armadilhas Extracelulares/metabolismo , Radicais Livres/metabolismo , Humanos , Necroptose/imunologia , Necrose/imunologia , Necrose/metabolismo , Ativação de Neutrófilo , Neutrófilos/imunologia , Neutrófilos/metabolismo , Fagocitose/imunologia , Piroptose/imunologia , Receptores de Morte Celular/metabolismo
16.
Fluids Barriers CNS ; 18(1): 15, 2021 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-33757539

RESUMO

The administration of microbial neuraminidase into the brain ventricular cavities of rodents represents a model of acute aseptic neuroinflammation. Ependymal cell death and hydrocephalus are unique features of this model. Here we demonstrate that activated microglia participates in ependymal cell death. Co-cultures of pure microglia with ependymal cells (both obtained from rats) were performed, and neuraminidase or lipopolysaccharide were used to activate microglia. Ependymal cell viability was unaltered in the absence of microglia or inflammatory stimulus (neuraminidase or lipopolysaccharide). The constitutive expression by ependymal cells of receptors for cytokines released by activated microglia, such as IL-1ß, was demonstrated by qPCR. Besides, neuraminidase induced the overexpression of both receptors in ventricular wall explants. Finally, ependymal viability was evaluated in the presence of functional blocking antibodies against IL-1ß and TNFα. In the co-culture setting, an IL-1ß blocking antibody prevented ependymal cell death, while TNFα antibody did not. These results suggest that activated microglia are involved in the ependymal damage that occurs after the administration of neuraminidase in the ventricular cavities, and points to IL-1ß as possible mediator of such effect. The relevance of these results lies in the fact that brain infections caused by neuraminidase-bearing pathogens are frequently associated to ependymal death and hydrocephalus.


Assuntos
Morte Celular/imunologia , Epêndima/imunologia , Microglia/imunologia , Neuraminidase/farmacologia , Animais , Células Cultivadas , Epêndima/citologia , Interleucina-1beta , Lipopolissacarídeos/farmacologia , Masculino , Ratos , Ratos Wistar
17.
Mol Cancer ; 20(1): 50, 2021 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-33685460

RESUMO

BACKGROUND: The mRNA-based cancer vaccine has been considered a promising strategy and the next hotspot in cancer immunotherapy. However, its application on cholangiocarcinoma remains largely uncharacterized. This study aimed to identify potential antigens of cholangiocarcinoma for development of anti-cholangiocarcinoma mRNA vaccine, and determine immune subtypes of cholangiocarcinoma for selection of suitable patients from an extremely heterogeneous population. METHODS: Gene expression profiles and corresponding clinical information were collected from GEO and TCGA, respectively. cBioPortal was used to visualize and compare genetic alterations. GEPIA2 was used to calculate the prognostic index of the selected antigens. TIMER was used to visualize the correlation between the infiltration of antigen-presenting cells and the expression of the identified antigens. Consensus clustering analysis was performed to identify the immune subtypes. Graph learning-based dimensionality reduction analysis was conducted to visualize the immune landscape of cholangiocarcinoma. RESULTS: Three tumor antigens, such as CD247, FCGR1A, and TRRAP, correlated with superior prognoses and infiltration of antigen-presenting cells were identified in cholangiocarcinoma. Cholangiocarcinoma patients were stratified into two immune subtypes characterized by differential molecular, cellular and clinical features. Patients with the IS1 tumor had immune "hot" and immunosuppressive phenotype, whereas those with the IS2 tumor had immune "cold" phenotype. Interestingly, patients with the IS2 tumor had a superior survival than those with the IS1 tumor. Furthermore, distinct expression of immune checkpoints and immunogenic cell death modulators was observed between different immune subtype tumors. Finally, the immune landscape of cholangiocarcinoma revealed immune cell components in individual patient. CONCLUSIONS: CD247, FCGR1A, and TRRAP are potential antigens for mRNA vaccine development against cholangiocarcinoma, specifically for patients with IS2 tumors. Therefore, this study provides a theoretical basis for the anti-cholangiocarcinoma mRNA vaccine and defines suitable patients for vaccination.


Assuntos
Antígenos de Neoplasias/imunologia , Neoplasias dos Ductos Biliares/etiologia , Vacinas Anticâncer/imunologia , Colangiocarcinoma/etiologia , Imunidade , RNA Mensageiro/genética , Pesquisa , Células Apresentadoras de Antígenos/imunologia , Células Apresentadoras de Antígenos/metabolismo , Antígenos de Neoplasias/genética , Neoplasias dos Ductos Biliares/metabolismo , Neoplasias dos Ductos Biliares/mortalidade , Neoplasias dos Ductos Biliares/terapia , Biomarcadores Tumorais , Vacinas Anticâncer/administração & dosagem , Morte Celular/genética , Morte Celular/imunologia , Colangiocarcinoma/metabolismo , Colangiocarcinoma/mortalidade , Colangiocarcinoma/terapia , Bases de Dados Genéticas , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Imunomodulação/genética , Imunoterapia/métodos , Mutação , Prognóstico , RNA Mensageiro/imunologia , Transcriptoma
18.
Plant Physiol ; 185(1): 240-255, 2021 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-33631806

RESUMO

In Arabidopsis (Arabidopsis thaliana), a hypersensitive-like response (HR-like response) is triggered underneath the eggs of the large white butterfly Pieris brassicae (P. brassicae), and this response is dependent on salicylic acid (SA) accumulation and signaling. Previous reports indicate that the clade I L-type LECTIN RECEPTOR KINASE-I.8 (LecRK-I.8) is involved in early steps of egg recognition. A genome-wide association study was used to better characterize the genetic structure of the HR-like response and discover loci that contribute to this response. We report here the identification of LecRK-I.1, a close homolog of LecRK-I.8, and show that two main haplotypes that explain part of the variation in HR-like response segregate among natural Arabidopsis accessions. Besides, signatures of balancing selection at this locus suggest that it may be ecologically important. Disruption of LecRK-I.1 results in decreased HR-like response and SA signaling, indicating that this protein is important for the observed responses. Furthermore, we provide evidence that LecRK-I.1 functions in the same signaling pathway as LecRK-I.8. Altogether, our results show that the response to eggs of P. brassicae is controlled by multiple LecRKs.


Assuntos
Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/imunologia , Morte Celular/genética , Morte Celular/imunologia , Imunidade Vegetal/genética , Imunidade Vegetal/imunologia , Proteínas Serina-Treonina Quinases/imunologia , Animais , Arabidopsis/genética , Arabidopsis/imunologia , Regulação da Expressão Gênica de Plantas , Genes de Plantas , Insetos/parasitologia , Óvulo
19.
Int J Mol Sci ; 22(2)2021 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-33440708

RESUMO

Calbindin-D28k (CB), a calcium-binding protein, mediates diverse neuronal functions. In this study, adult gerbils were fed a normal diet (ND) or exposed to intermittent fasting (IF) for three months, and were randomly assigned to sham or ischemia operated groups. Ischemic injury was induced by transient forebrain ischemia for 5 min. Short-term memory was examined via passive avoidance test. CB expression was investigated in the Cornu Ammonis 1 (CA1) region of the hippocampus via western blot analysis and immunohistochemistry. Finally, histological analysis was used to assess neuroprotection and gliosis (microgliosis and astrogliosis) in the CA1 region. Short-term memory did not vary significantly between ischemic gerbils with IF and those exposed to ND. CB expression was increased significantly in the CA1 pyramidal neurons of ischemic gerbils with IF compared with that of gerbils fed ND. However, the CB expression was significantly decreased in ischemic gerbils with IF, similarly to that of ischemic gerbils exposed to ND. The CA1 pyramidal neurons were not protected from ischemic injury in both groups, and gliosis (astrogliosis and microgliosis) was gradually increased with time after ischemia. In addition, immunoglobulin G was leaked into the CA1 parenchyma from blood vessels and gradually increased with time after ischemic insult in both groups. Taken together, our study suggests that IF for three months increases CB expression in hippocampal CA1 pyramidal neurons; however, the CA1 pyramidal neurons are not protected from transient forebrain ischemia. This failure in neuroprotection may be attributed to disruption of the blood-brain barrier, which triggers gliosis after ischemic insults.


Assuntos
Calbindina 1/genética , Jejum , Expressão Gênica , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/metabolismo , Animais , Calbindina 1/imunologia , Morte Celular/genética , Morte Celular/imunologia , Gerbillinae , Gliose/etiologia , Imunoglobulina G/imunologia , Masculino , Neurônios/metabolismo , Neurônios/patologia , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/patologia
20.
Nat Rev Immunol ; 21(4): 257-267, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33077935

RESUMO

Following their exit from the thymus, T cells are endowed with potent effector functions but must spare host tissue from harm. The fate of these cells is dictated by a series of checkpoints that regulate the quality and magnitude of T cell-mediated immunity, known as tolerance checkpoints. In this Perspective, we discuss the mediators and networks that control the six main peripheral tolerance checkpoints throughout the life of a T cell: quiescence, ignorance, anergy, exhaustion, senescence and death. At the naive T cell stage, two intrinsic checkpoints that actively maintain tolerance are quiescence and ignorance. In the presence of co-stimulation-deficient T cell activation, anergy is a dominant hallmark that mandates T cell unresponsiveness. When T cells are successfully stimulated and reach the effector stage, exhaustion and senescence can limit excessive inflammation and prevent immunopathology. At every stage of the T cell's journey, cell death exists as a checkpoint to limit clonal expansion and to terminate unrestrained responses. Here, we compare and contrast the T cell tolerance checkpoints and discuss their specific roles, with the aim of providing an integrated view of T cell peripheral tolerance and fate regulation.


Assuntos
Apoptose/imunologia , Senescência Celular/imunologia , Anergia Clonal/imunologia , Memória Imunológica/imunologia , Tolerância Periférica/imunologia , Linfócitos T/imunologia , Morte Celular/imunologia , Humanos
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