RESUMO
Mitochondria are multi-functioning organelles that participate in a wide range of biologic processes from energy metabolism to cellular suicide. Mitochondria are also involved in the cellular innate immune response against microorganisms or environmental irritants, particularly in mammals. Mitochondrial-mediated innate immunity is achieved by the activation of two discrete signaling pathways, the NLR family pyrin domain-containing 3 inflammasomes and the retinoic acid-inducible gene I-like receptor pathway. In both pathways, a mitochondrial outer membrane adaptor protein, called mitochondrial antiviral signaling MAVS, and mitochondria-derived components play a key role in signal transduction. In this review, we discuss current insights regarding the fundamental phenomena of mitochondrial-related innate immune responses, and review the specific roles of various mitochondrial subcompartments in fine-tuning innate immune signaling events. We propose that specific targeting of mitochondrial functions is a potential therapeutic approach for the management of infectious diseases and autoinflammatory disorders with an excessive immune response.
Assuntos
Interações Hospedeiro-Patógeno/imunologia , Imunidade Inata , Mitocôndrias/imunologia , Infecções por Vírus de RNA/imunologia , Vírus de RNA/imunologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Animais , Proteína DEAD-box 58/genética , Proteína DEAD-box 58/imunologia , Regulação da Expressão Gênica , Interações Hospedeiro-Patógeno/genética , Humanos , Inflamassomos , MicroRNAs/genética , MicroRNAs/imunologia , Mitocôndrias/genética , Mitocôndrias/virologia , Membranas Mitocondriais/imunologia , Membranas Mitocondriais/virologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Infecções por Vírus de RNA/genética , Infecções por Vírus de RNA/patologia , Infecções por Vírus de RNA/virologia , Vírus de RNA/genética , Vírus de RNA/patogenicidade , Receptores Imunológicos/genética , Receptores Imunológicos/imunologia , Transdução de SinaisRESUMO
In the tumour microenvironment (TME), immunogenic cell death (ICD) plays a major role in stimulating the dysfunctional antitumour immune system. Chronic exposure of damage-associated molecular patterns (DAMPs) attracts receptors and ligands on dendritic cells (DCs) and activates immature DCs to transition to a mature phenotype, which promotes the processing of phagocytic cargo in DCs and accelerates the engulfment of antigenic components by DCs. Consequently, via antigen presentation, DCs stimulate specific T cell responses that kill more cancer cells. The induction of ICD eventually results in long-lasting protective antitumour immunity. Through the exploration of ICD inducers, recent studies have shown that there are many novel modalities with the ability to induce immunogenic cancer cell death. In this review, we mainly discussed and summarized the emerging methods for inducing immunogenic cancer cell death. Concepts and molecular mechanisms relevant to antitumour effects of ICD are also briefly discussed.
Assuntos
Antineoplásicos/uso terapêutico , Células Dendríticas/imunologia , Morte Celular Imunogênica/genética , Neoplasias/imunologia , Neoplasias/terapia , Linfócitos T/imunologia , Microambiente Tumoral/imunologia , Animais , Antineoplásicos/farmacologia , Calreticulina/genética , Calreticulina/metabolismo , Terapia Combinada , Estresse do Retículo Endoplasmático/imunologia , Humanos , Imunoterapia , Membranas Mitocondriais/imunologia , Membranas Mitocondriais/metabolismo , Nanopartículas/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Fototerapia , Microambiente Tumoral/genéticaRESUMO
We investigated the effect of apigenin, a dietary flavonoid, on isoproterenol hydrochloride (ISO)-induced apoptotic signaling in cardiomyoblast H9C2 cells. The results showed that apigenin treatment (10 µM) prevented ISO (31.25 µM)-induced lipid peroxidative levels and antioxidants status in H9C2 cells. Furthermore, apigenin inhibited expression of inflammatory markers in ISO-treated cells. In addition, apigenin prevented ISO-induced DNA damage and apoptotic signaling through modulating the expression of Bax, caspase-3, -8 and -9, cytochrome c, and Fas proteins in H9C2 cells. It is concluded that apigenin prevents ISO-induced antioxidants depletion, oxidative DNA damage, inflammatory, and apoptotic signaling in H9C2 cells. Thus, the present results demonstrated that apigenin has a cardioprotective effect on cardiomyoblasts cells.
Assuntos
Antioxidantes/farmacologia , Apigenina/farmacologia , Apoptose/efeitos dos fármacos , Cardiotônicos/efeitos adversos , Isoproterenol/efeitos adversos , Mioblastos Cardíacos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Biomarcadores/metabolismo , Cardiotônicos/antagonistas & inibidores , Linhagem Celular , Dano ao DNA/efeitos dos fármacos , Mediadores da Inflamação/agonistas , Mediadores da Inflamação/antagonistas & inibidores , Mediadores da Inflamação/metabolismo , Isoproterenol/antagonistas & inibidores , Peroxidação de Lipídeos/efeitos dos fármacos , Potencial da Membrana Mitocondrial , Mitocôndrias Cardíacas/efeitos dos fármacos , Mitocôndrias Cardíacas/imunologia , Mitocôndrias Cardíacas/metabolismo , Membranas Mitocondriais/efeitos dos fármacos , Membranas Mitocondriais/imunologia , Membranas Mitocondriais/metabolismo , Mioblastos Cardíacos/citologia , Mioblastos Cardíacos/imunologia , Mioblastos Cardíacos/metabolismo , Ratos , Proteína X Associada a bcl-2/agonistas , Proteína X Associada a bcl-2/antagonistas & inibidores , Proteína X Associada a bcl-2/metabolismo , Receptor fas/agonistas , Receptor fas/antagonistas & inibidores , Receptor fas/metabolismoRESUMO
Apoptosis represents a key anti-cancer therapeutic effector mechanism. During apoptosis, mitochondrial outer membrane permeabilization (MOMP) typically kills cells even in the absence of caspase activity. Caspase activity can also have a variety of unwanted consequences that include DNA damage. We therefore investigated whether MOMP-induced caspase-independent cell death (CICD) might be a better way to kill cancer cells. We find that cells undergoing CICD display potent pro-inflammatory effects relative to apoptosis. Underlying this, MOMP was found to stimulate NF-κB activity through the downregulation of inhibitor of apoptosis proteins. Strikingly, engagement of CICD displays potent anti-tumorigenic effects, often promoting complete tumour regression in a manner dependent on intact immunity. Our data demonstrate that by activating NF-κB, MOMP can exert additional signalling functions besides triggering cell death. Moreover, they support a rationale for engaging caspase-independent cell death in cell-killing anti-cancer therapies.
Assuntos
Caspases/metabolismo , Neoplasias do Colo/enzimologia , Mediadores da Inflamação/metabolismo , Mitocôndrias/enzimologia , Membranas Mitocondriais/enzimologia , NF-kappa B/metabolismo , Compostos de Anilina/farmacologia , Animais , Antineoplásicos/farmacologia , Apoptose , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/imunologia , Neoplasias do Colo/patologia , Genótipo , Células HeLa , Humanos , Proteínas Inibidoras de Apoptose/metabolismo , Ativação de Macrófagos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/imunologia , Mitocôndrias/patologia , Membranas Mitocondriais/efeitos dos fármacos , Membranas Mitocondriais/imunologia , Membranas Mitocondriais/patologia , NF-kappa B/deficiência , Necrose , Permeabilidade , Fenótipo , Proteínas Serina-Treonina Quinases/metabolismo , Interferência de RNA , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Transdução de Sinais , Sulfonamidas/farmacologia , Fatores de Tempo , Transfecção , Fator de Necrose Tumoral alfa/metabolismo , Quinase Induzida por NF-kappaBRESUMO
Recent evidence indicates that mitochondria lie at the heart of immunity. Mitochondrial DNA acts as a danger-associated molecular pattern (DAMP), and the mitochondrial outer membrane is a platform for signaling molecules such as MAVS in RIG-I signaling, and for the NLRP3 inflammasome. Mitochondrial biogenesis, fusion and fission have roles in aspects of immune-cell activation. Most important, Krebs cycle intermediates such as succinate, fumarate and citrate engage in processes related to immunity and inflammation, in both innate and adaptive immune cells. These discoveries are revealing mitochondrial targets that could potentially be exploited for therapeutic gain in inflammation and cancer.
Assuntos
Imunidade Adaptativa , Ciclo do Ácido Cítrico/imunologia , Imunidade Inata , Mitocôndrias/imunologia , Membranas Mitocondriais/imunologia , Animais , Proteína DEAD-box 58/metabolismo , Metabolismo Energético , Humanos , Imunomodulação , Inflamassomos/metabolismo , Ativação Linfocitária , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Receptores Imunológicos , Receptores de Reconhecimento de Padrão/metabolismo , Transdução de SinaisRESUMO
Mitochondria have emerged as critical platforms for antiviral innate immune signaling. This is due in large part to the mitochondrial localization of the innate immune signaling adaptor MAVS (mitochondrial antiviral signaling protein), which coordinates signals received from two independent cytosolic pathogen recognition receptors (PRRs) to induce antiviral genes. The existence of a shared adaptor for two central PRRs presents an ideal target by which the host cell can prevent cellular damage induced by uncontrolled inflammation through alteration of MAVS expression and/or signaling. In this review, we focus on the MAVS regulome and review the cellular factors that regulate MAVS by (1) protein-protein interactions, (2) alterations in mitochondrial dynamics, and/or (3) post-translational modifications.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Imunidade Inata , Processamento de Proteína Pós-Traducional , Regulon/imunologia , Vírus/imunologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Antivirais/imunologia , Antivirais/metabolismo , Regulação da Expressão Gênica , Humanos , Mitocôndrias/imunologia , Mitocôndrias/metabolismo , Membranas Mitocondriais/imunologia , Membranas Mitocondriais/metabolismo , Modelos Moleculares , Mapas de Interação de Proteínas , Transdução de Sinais/imunologiaRESUMO
Arenaviruses perturb innate antiviral defense by blocking induction of type I interferon (IFN) production. Accordingly, the arenavirus nucleoprotein (NP) was shown to block activation and nuclear translocation of interferon regulatory factor 3 (IRF3) in response to virus infection. Here, we sought to identify cellular factors involved in innate antiviral signaling targeted by arenavirus NP. Consistent with previous studies, infection with the prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) prevented phosphorylation of IRF3 in response to infection with Sendai virus, a strong inducer of the retinoic acid-inducible gene I (RIG-I)/mitochondrial antiviral signaling (MAVS) pathway of innate antiviral signaling. Using a combination of coimmunoprecipitation and confocal microscopy, we found that LCMV NP associates with the IκB kinase (IKK)-related kinase IKKε but that, rather unexpectedly, LCMV NP did not bind to the closely related TANK-binding kinase 1 (TBK-1). The NP-IKKε interaction was highly conserved among arenaviruses from different clades. In LCMV-infected cells, IKKε colocalized with NP but not with MAVS located on the outer membrane of mitochondria. LCMV NP bound the kinase domain (KD) of IKKε (IKBKE) and blocked its autocatalytic activity and its ability to phosphorylate IRF3, without undergoing phosphorylation. Together, our data identify IKKε as a novel target of arenavirus NP. Engagement of NP seems to sequester IKKε in an inactive complex. Considering the important functions of IKKε in innate antiviral immunity and other cellular processes, the NP-IKKε interaction likely plays a crucial role in arenavirus-host interaction.
Assuntos
Quinase I-kappa B/metabolismo , Fator Regulador 3 de Interferon/metabolismo , Coriomeningite Linfocítica/metabolismo , Vírus da Coriomeningite Linfocítica/metabolismo , Complexos Multiproteicos/metabolismo , Proteínas do Nucleocapsídeo/metabolismo , Linhagem Celular Tumoral , Proteína DEAD-box 58 , RNA Helicases DEAD-box/genética , RNA Helicases DEAD-box/imunologia , RNA Helicases DEAD-box/metabolismo , Células HEK293 , Humanos , Quinase I-kappa B/genética , Quinase I-kappa B/imunologia , Imunidade Inata/genética , Fator Regulador 3 de Interferon/genética , Fator Regulador 3 de Interferon/imunologia , Coriomeningite Linfocítica/genética , Coriomeningite Linfocítica/imunologia , Vírus da Coriomeningite Linfocítica/genética , Vírus da Coriomeningite Linfocítica/imunologia , Membranas Mitocondriais/imunologia , Membranas Mitocondriais/metabolismo , Complexos Multiproteicos/genética , Complexos Multiproteicos/imunologia , Proteínas do Nucleocapsídeo/genética , Proteínas do Nucleocapsídeo/imunologia , Fosforilação/genética , Fosforilação/imunologia , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/imunologia , Proteínas Serina-Treonina Quinases/metabolismo , Receptores Imunológicos , Vírus Sendai/genética , Vírus Sendai/imunologia , Vírus Sendai/metabolismoRESUMO
Hepatitis C virus (HCV) elevated expression of the translocase of outer mitochondrial membrane 70 (Tom70). Interestingly, overexpression of Tom70 induces interferon (IFN) synthesis in hepatocytes, and it was impaired by HCV. Here, we addressed the mechanism of this impairment. The HCV NS3/4A protein induced Tom70 expression. The HCV NS3 protein interacted in cells, and cleaved the adapter protein mitochondrial anti-viral signaling (MAVS). Ectopic overexpression of Tom70 could not inhibit this cleavage. As a result, IRF-3 phosphorylation was impaired and IFN-ß induction was suppressed. These results indicate that MAVS works upstream of Tom70 and the cleavage of MAVS by HCV NS3 protease suppresses signaling of IFN induction.
Assuntos
Hepacivirus/patogenicidade , Tolerância Imunológica , Interferons/imunologia , Proteínas de Transporte da Membrana Mitocondrial/imunologia , Membranas Mitocondriais/imunologia , Proteínas não Estruturais Virais/metabolismo , Células Hep G2 , Hepacivirus/imunologia , Hepatócitos/imunologia , Hepatócitos/virologia , Humanos , Evasão da Resposta Imune , Interferons/antagonistas & inibidores , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Proteínas do Complexo de Importação de Proteína Precursora Mitocondrial , Proteínas não Estruturais Virais/imunologiaRESUMO
Sensing of RNA virus infection by the RIG-I-like receptors (RLRs) engages a complex signaling cascade that utilizes the mitochondrial antiviral signaling (MAVS) adapter protein to orchestrate the innate host response to pathogen, ultimately leading to the induction of antiviral and inflammatory responses mediated by type I interferon (IFN) and NF-κB pathways. MAVS is localized to the outer mitochondrial membrane, and has been associated with peroxisomes, the endoplasmic reticulum and autophagosomes, where it coordinates signaling events downstream of RLRs. MAVS not only plays a pivotal role in the induction of antiviral and inflammatory pathways but is also involved in the coordination of apoptotic and metabolic functions. This review summarizes recent findings related to the MAVS adapter and its essential role in the innate immune response to RNA viruses.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/imunologia , Imunidade Inata , Mitocôndrias/imunologia , Infecções por Vírus de RNA/imunologia , Vírus de RNA/imunologia , Transdução de Sinais/imunologia , Fatores de Transcrição/imunologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Apoptose/imunologia , RNA Helicases DEAD-box/imunologia , RNA Helicases DEAD-box/metabolismo , Retículo Endoplasmático/imunologia , Retículo Endoplasmático/metabolismo , Humanos , Interferon Tipo I/imunologia , Interferon Tipo I/metabolismo , Helicase IFIH1 Induzida por Interferon , Mitocôndrias/metabolismo , Membranas Mitocondriais/imunologia , Membranas Mitocondriais/metabolismo , NF-kappa B/imunologia , NF-kappa B/metabolismo , Peroxissomos/imunologia , Peroxissomos/metabolismo , RNA Helicases/imunologia , RNA Helicases/metabolismo , Infecções por Vírus de RNA/virologia , RNA Viral/imunologia , Transativadores , Fatores de Transcrição/metabolismoRESUMO
Intercellular communication is an essential process in stimulating lymphocyte development and in activating and shaping an immune response. B cell development requires cell-to-cell contact with and cytokine production by bone marrow stromal cells. However, this intimate relationship also may be responsible for the transfer of death-inducing molecules to the B cells. 7,12-Dimethylbenz[a]anthracene (DMBA), a prototypical polycyclic aromatic hydrocarbon, activates caspase-3 in pro/pre-B cells in a bone marrow stromal cell-dependent manner, resulting in apoptosis. These studies were designed to examine the hypothesis that an intrinsic apoptotic pathway is activated by DMBA and that the ultimate death signal is a DMBA metabolite generated by the stromal cells and transferred to the B cells. Although a loss of mitochondrial membrane potential did not occur in the DMBA/stromal cell-induced pathway, cytochrome c release was stimulated in B cells. Caspase-9 was activated, and formation of the apoptosome was required to support apoptosis, as demonstrated by the suppression of death in Apaf-1(fog) mutant pro-B cells. Investigation of signaling upstream of the mitochondria demonstrated an essential role for p53. Furthermore, DMBA-3,4-dihydrodiol-1,2-epoxide, a DNA-reactive metabolite of DMBA, was sufficient to upregulate p53, induce caspase-9 cleavage, and initiate B cell apoptosis in the absence of stromal cells, suggesting that production of this metabolite by the stromal cells and transfer to the B cells are proximal events in triggering apoptosis. Indeed, we provide evidence that metabolite transfer from bone marrow stromal cells occurs through membrane exchange, which may represent a novel communication mechanism between developing B cells and stromal cells.
Assuntos
9,10-Dimetil-1,2-benzantraceno/farmacologia , Apoptose/imunologia , Subpopulações de Linfócitos B/efeitos dos fármacos , Subpopulações de Linfócitos B/imunologia , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/imunologia , Comunicação Celular/imunologia , Transdução de Sinais/imunologia , 9,10-Dimetil-1,2-benzantraceno/metabolismo , Animais , Apoptose/efeitos dos fármacos , Subpopulações de Linfócitos B/metabolismo , Células da Medula Óssea/metabolismo , Comunicação Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Morte Celular/imunologia , Linhagem Celular , Técnicas de Cocultura , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Membranas Mitocondriais/efeitos dos fármacos , Membranas Mitocondriais/imunologia , Membranas Mitocondriais/metabolismo , Transdução de Sinais/efeitos dos fármacos , Células-Tronco/efeitos dos fármacos , Células-Tronco/imunologia , Células-Tronco/metabolismo , Células Estromais/efeitos dos fármacos , Células Estromais/imunologia , Células Estromais/metabolismo , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologiaRESUMO
We have generated hexavalent antibodies (HexAbs) comprising 6 Fabs tethered to one Fc of human IgG1. Three such constructs, 20-20, a monospecific HexAb comprising 6 Fabs of veltuzumab (humanized anti-CD20 immunoglobulin G1κ [IgG1κ]), 20-22, a bispecific HexAb comprising veltuzumab and 4 Fabs of epratuzumab (humanized anti-CD22 IgG1κ), and 22-20, a bispecific HexAb comprising epratuzumab and 4 Fabs of veltuzumab, were previously shown to inhibit pro-liferation of several lymphoma cell lines at nanomolar concentrations in the absence of a crosslinking antibody. We now report an in-depth analysis of the apoptotic and survival signals induced by the 3 HexAbs in Burkitt lymphomas and provide in vitro cytotoxicity data for additional lymphoma cell lines and also chronic lymphocytic leukemia patient specimens. Among the key findings are the significant increase in the levels of phosphorylated p38 and phosphatase and tensin homolog deleted on chromosome 10 (PTEN) by all 3 HexAbs and the notable differences in the signaling events triggered by the HexAbs from those incurred by crosslinking veltuzumab or rituximab with a secondary antibody. Thus, the greatly enhanced direct toxicity of these HexAbs correlates with their ability to alter the basal expression of various intracellular proteins involved in regulating cell growth, survival, and apoptosis, with the net outcome leading to cell death.
Assuntos
Anticorpos Monoclonais/imunologia , Antígenos CD20/imunologia , Antineoplásicos/imunologia , Leucemia/imunologia , Linfoma de Células B/imunologia , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico/imunologia , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Anticorpos Monoclonais Murinos/imunologia , Anticorpos Monoclonais Murinos/uso terapêutico , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Leucemia/tratamento farmacológico , Linfoma de Células B/tratamento farmacológico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Membranas Mitocondriais/efeitos dos fármacos , Membranas Mitocondriais/imunologia , NF-kappa B/imunologia , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/imunologia , Proteínas Proto-Oncogênicas c-bcl-2/imunologia , Rituximab , Transdução de SinaisRESUMO
Premature death of the adoptively transferred cytolytic T lymphocytes (CTL) by means of activation induced cell death (AICD) represents one of the major constraints in devising an effective anti-cancer immune intervention strategy. Understanding the mechanism of AICD is, therefore, critical for developing methods to interfere with this death process. Although the existing paradigm on AICD centers around the initiation of the cascade of events originating from the engagement of death receptors leading to the activation of effector caspases and eventually resulting in cell death, recent findings have questioned the universal role of caspases as the cell death executioners. We here review our current understanding of the contribution of caspase-dependent and caspase-independent death executioners in AICD of T cells. We will also discuss the involvement of mitochondria-centric death pathway in AICD of human tumor associated antigen-specific primary CTL and its implications in cancer immunotherapy.
Assuntos
Apoptose/imunologia , Caspases/imunologia , Imunoterapia , Mitocôndrias/imunologia , Neoplasias/terapia , Linfócitos T Citotóxicos/imunologia , Transferência Adotiva , Caspases/metabolismo , Permeabilidade da Membrana Celular , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/imunologia , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Membranas Mitocondriais/imunologia , Membranas Mitocondriais/metabolismo , Neoplasias/imunologiaRESUMO
The innate immune system is essential for the initial detection of invading viruses and subsequent activation of adaptive immunity. Three classes of receptors, designated retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs), Toll-like receptors (TLRs), and nucleotide oligomerization domain (NOD)-like receptors (NLRs), sense viral components, such as double-stranded RNA (dsRNA), single-stranded RNA, and DNA. RLRs and TLRs play essential roles in the production of type I interferons (IFNs) and proinflammatory cytokines in cell type-specific manners. While the RLRs play essential roles in the recognition of RNA viruses in various cells, plasmacytoid dendritic cells utilize TLRs for detecting virus invasion. NLRs play a role in the production of mature interleukin-1 beta to dsRNA stimulation. Activation of innate immune cells is critical for mounting adaptive immune responses. In this review, we discuss recent advances in our understanding of the mechanisms of viral RNA recognition by these different types of receptors and its relation to acquired immune responses.
Assuntos
RNA Helicases DEAD-box/metabolismo , Imunidade Inata , RNA Helicases/metabolismo , Infecções por Vírus de RNA/imunologia , RNA Viral/imunologia , RNA Viral/metabolismo , Animais , Proteína DEAD-box 58 , RNA Helicases DEAD-box/genética , RNA Helicases DEAD-box/imunologia , Endorribonucleases/imunologia , Endorribonucleases/metabolismo , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunidade Celular , Interferon Tipo I/imunologia , Helicase IFIH1 Induzida por Interferon , Membranas Mitocondriais/imunologia , Proteínas Mitocondriais/imunologia , RNA Helicases/genética , RNA Helicases/imunologia , Infecções por Vírus de RNA/fisiopatologia , Infecções por Vírus de RNA/prevenção & controle , Vírus de RNA/fisiologia , RNA Viral/genética , Receptores Imunológicos , Transdução de Sinais/imunologia , Ubiquitinação/imunologiaRESUMO
The phagocyte NADPH oxidase is a multicomponent enzyme complex mediating microbial killing. We find that NADPH oxidase p47(phox)-deficient (p47(phox-/-)) chronic granulomatous disease (CGD) mice develop lymph node hyperplasia even without obvious infection, where increased number of T and B lymphocytes is associated with increased percent of naïve cells and a lower T : B cell ratio than wild type. Paradoxically, despite lymphoid hyperplasia in vivo, when lymphocytes are placed in culture, p47(phox-/-) CD8(+) lymphocytes progress more rapidly to apoptosis than wild type. This is associated in cultured p47(phox-/-) CD8(+) lymphocytes with the induction of proapoptotic Bim and Puma expression, increased mitochondrial outer membrane permeabilization and depressed Bcl-2 expression. Addition of IL-7 to the culture partially corrects Bcl-2 levels in cultured p47(phox-/-) CD8(+) lymphocytes and improves the survival. Adding glucose oxidase to the culture to generate hydrogen peroxide along with IL-7 further improves p47(phox-/-) CD8(+) lymphocyte survival, but only to 30% of wild type. We conclude that p47(phox-/-) CD8(+) lymphocytes have an intrinsic survival defect likely in part related to the oxidase deficiency, but in vivo in lymph nodes of CGD mice, there are microenvironmental factors yet to be delineated that suppress the progression of apoptosis and allow the accumulation of lymphocytes leading to lymphoid hyperplasia.
Assuntos
Apoptose/imunologia , Doença Granulomatosa Crônica/imunologia , Linfonodos/imunologia , NADPH Oxidases/imunologia , Linfócitos T/imunologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Proteínas Reguladoras de Apoptose/biossíntese , Proteínas Reguladoras de Apoptose/imunologia , Linfócitos B/enzimologia , Linfócitos B/imunologia , Linfócitos B/patologia , Proteína 11 Semelhante a Bcl-2 , Permeabilidade da Membrana Celular/efeitos dos fármacos , Permeabilidade da Membrana Celular/genética , Permeabilidade da Membrana Celular/imunologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/imunologia , Células Cultivadas , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/imunologia , Glucose Oxidase , Doença Granulomatosa Crônica/enzimologia , Doença Granulomatosa Crônica/genética , Doença Granulomatosa Crônica/patologia , Peróxido de Hidrogênio , Hiperplasia/enzimologia , Hiperplasia/genética , Hiperplasia/imunologia , Hiperplasia/patologia , Interleucina-7/imunologia , Interleucina-7/farmacologia , Linfonodos/enzimologia , Linfonodos/patologia , Proteínas de Membrana/biossíntese , Proteínas de Membrana/imunologia , Camundongos , Camundongos Knockout , Membranas Mitocondriais/enzimologia , Membranas Mitocondriais/imunologia , NADPH Oxidases/genética , Proteínas Proto-Oncogênicas/biossíntese , Proteínas Proto-Oncogênicas/imunologia , Proteínas Proto-Oncogênicas c-bcl-2/imunologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Linfócitos T/enzimologia , Linfócitos T/patologia , Proteínas Supressoras de Tumor/biossíntese , Proteínas Supressoras de Tumor/imunologiaRESUMO
Remarkably, apoptosis was induced by exposing peritoneal resident macrophages (PRM) of C3H mice, but not other strains of mice, to ionizing radiation. The molecular mechanism of this strain-specific apoptosis in PRM was studied. The apoptosis elicited in C3H mouse PRM 4 h after exposure was effectively blocked by proteasome inhibitors. Irradiation-induced disruption of mitochondrial transmembrane potential and the release of cytochrome c into the cytosol were also suppressed by a proteasome inhibitor but not by a caspase inhibitor. To determine whether the apoptosis occurred due to a depletion of antiapoptotic proteins, Bcl-2 family proteins were examined. Irradiation markedly decreased the level of Mcl-1, but not Bcl-2, Bcl-X(L), Bax, A1, or cIAP1. Mcl-1's depletion was suppressed by a proteasome inhibitor but not by a caspase inhibitor. The amount of Mcl-1 was well correlated with the rate of apoptosis in C3H mouse PRM exposed to irradiation and not affected by irradiation in radioresistant B6 mouse PRM. Irradiation increased rather than decreased the Mcl-1 mRNA expression in C3H mouse PRM. On the other hand, Mcl-1 protein synthesis was markedly suppressed by irradiation. Global protein synthesis was also suppressed by irradiation in C3H mouse PRM but not in B6 mouse PRM. The down-regulation of Mcl-1 expression with Mcl-1-specific small interfering RNA or antisense oligonucleotide significantly induced apoptosis in both C3H and B6 mouse PRM without irradiation. It was concluded that the apoptosis elicited in C3H mouse PRM by ionizing radiation was attributable to the depletion of Mcl-1 through radiation-induced arrest of global protein synthesis.
Assuntos
Proteínas Reguladoras de Apoptose/biossíntese , Apoptose/efeitos da radiação , Regulação para Baixo/efeitos da radiação , Raios gama , Macrófagos Peritoneais/metabolismo , Biossíntese de Proteínas/efeitos da radiação , Animais , Apoptose/efeitos dos fármacos , Apoptose/imunologia , Proteínas Reguladoras de Apoptose/imunologia , Inibidores de Caspase , Caspases/metabolismo , Citocromos c/imunologia , Citocromos c/metabolismo , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/imunologia , Feminino , Macrófagos Peritoneais/imunologia , Camundongos , Camundongos Endogâmicos C3H , Membranas Mitocondriais/imunologia , Membranas Mitocondriais/metabolismo , Proteína de Sequência 1 de Leucemia de Células Mieloides , Proteínas de Neoplasias , Inibidores de Proteases/farmacologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma , Biossíntese de Proteínas/efeitos dos fármacos , Biossíntese de Proteínas/imunologia , Proteínas Proto-Oncogênicas c-bcl-2 , RNA Interferente Pequeno/imunologia , RNA Interferente Pequeno/farmacologia , Especificidade da EspécieRESUMO
Immunological and virological events that occur during the earliest stages of SIV infection are now considered to have a major impact on subsequent disease progression. In the present study, we demonstrate a clear correlation between progression to AIDS and the rate of in vitro CD4+ (but not CD8+) T cell death in lymph nodes. The dying CD4+ T cells were effector memory T cells, which are critical for the immune response to pathogens. However, there was no correlation between the rate of the viral replication within lymph nodes and the extent of Fas ligand-mediated death, despite the increased sensitivity of CD4+ T cells to death in response to recombinant human Fas ligand. CD4+ T cell death was caspase and apoptosis-inducing factor independent but was clearly associated with mitochondrion damage. Interestingly, higher expression levels of the active form of Bak, a proapoptotic molecule involved in mitochondrial membrane permeabilization, were observed in SIV-infected macaques progressing more rapidly to AIDS. Finally, we demonstrated that the strain of SIV we used requires CCR5 and BOB/GRP15 molecules as coreceptors and caused death of unstimulated noncycling primary CD4+ T cells. Altogether, these results demonstrate that CD4+ T cell death occurring early after SIV infection is a crucial determinant of progression to AIDS and that it is mediated by the intrinsic death pathway.