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1.
Nat Commun ; 11(1): 3806, 2020 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-32732922

RESUMO

Most triple-negative breast cancer (TNBC) patients fail to respond to T cell-mediated immunotherapies. Unfortunately, the molecular determinants are still poorly understood. Breast cancer is the disease genetically linked to a deficiency in autophagy. Here, we show that autophagy defects in TNBC cells inhibit T cell-mediated tumour killing in vitro and in vivo. Mechanistically, we identify Tenascin-C as a candidate for autophagy deficiency-mediated immunosuppression, in which Tenascin-C is Lys63-ubiquitinated by Skp2, particularly at Lys942 and Lys1882, thus promoting its recognition by p62 and leading to its selective autophagic degradation. High Tenascin-C expression is associated with poor prognosis and inversely correlated with LC3B expression and CD8+ T cells in TNBC patients. More importantly, inhibition of Tenascin-C in autophagy-impaired TNBC cells sensitizes T cell-mediated tumour killing and improves antitumour effects of single anti-PD1/PDL1 therapy. Our results provide a potential strategy for targeting TNBC with the combination of Tenascin-C blockade and immune checkpoint inhibitors.


Assuntos
Autofagia/imunologia , Linfócitos T CD8-Positivos/imunologia , Tenascina/metabolismo , Neoplasias de Mama Triplo Negativas/imunologia , Evasão Tumoral/imunologia , Animais , Antineoplásicos Imunológicos/farmacologia , Autofagia/genética , Antígeno B7-H1/antagonistas & inibidores , Linfócitos T CD8-Positivos/transplante , Linhagem Celular Tumoral , Feminino , Células HEK293 , Humanos , Imunoterapia Adotiva , Camundongos , Camundongos Endogâmicos BALB C , Camundongos SCID , Prognóstico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Interferência de RNA , RNA Interferente Pequeno/genética , Proteínas de Ligação a RNA/metabolismo , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/terapia , Evasão Tumoral/genética
2.
Cells ; 9(9)2020 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-32847034

RESUMO

The preservation of cellular homeostasis requires the synthesis of new proteins (proteostasis) and organelles, and the effective removal of misfolded or impaired proteins and cellular debris. This cellular homeostasis involves two key proteostasis mechanisms, the ubiquitin proteasome system and the autophagy-lysosome pathway. These catabolic pathways have been known to be involved in respiratory exacerbations and the pathogenesis of various lung diseases, such as chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), idiopathic pulmonary fibrosis (IPF), acute lung injury (ALI), acute respiratory distress syndrome (ARDS), and coronavirus disease-2019 (COVID-19). Briefly, proteostasis and autophagy processes are known to decline over time with age, cigarette or biomass smoke exposure, and/or influenced by underlying genetic factors, resulting in the accumulation of misfolded proteins and cellular debris, elevating apoptosis and cellular senescence, and initiating the pathogenesis of acute or chronic lung disease. Moreover, autophagic dysfunction results in an impaired microbial clearance, post-bacterial and/or viral infection(s) which contribute to the initiation of acute and recurrent respiratory exacerbations as well as the progression of chronic obstructive and restrictive lung diseases. In addition, the autophagic dysfunction-mediated cystic fibrosis transmembrane conductance regulator (CFTR) immune response impairment further exacerbates the lung disease. Recent studies demonstrate the therapeutic potential of novel autophagy augmentation strategies, in alleviating the pathogenesis of chronic obstructive or restrictive lung diseases and exacerbations such as those commonly seen in COPD, CF, ALI/ARDS and COVID-19.


Assuntos
Autofagia/imunologia , Betacoronavirus , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/metabolismo , Progressão da Doença , Pneumonia Viral/imunologia , Pneumonia Viral/metabolismo , Lesão Pulmonar Aguda/imunologia , Lesão Pulmonar Aguda/metabolismo , Infecções por Coronavirus/virologia , Fibrose Cística/imunologia , Fibrose Cística/metabolismo , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Homeostase , Humanos , Fibrose Pulmonar Idiopática/imunologia , Fibrose Pulmonar Idiopática/metabolismo , Lisossomos/metabolismo , Pandemias , Pneumonia Viral/virologia , Doença Pulmonar Obstrutiva Crônica/imunologia , Doença Pulmonar Obstrutiva Crônica/metabolismo , Síndrome do Desconforto Respiratório do Adulto/imunologia , Síndrome do Desconforto Respiratório do Adulto/metabolismo
3.
Arch Virol ; 165(10): 2165-2176, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32740830

RESUMO

The PI3K/Akt signalling pathway is a crucial signalling cascade that regulates transcription, protein translation, cell growth, proliferation, cell survival, and metabolism. During viral infection, viruses exploit a variety of cellular pathways, including the well-known PI3K/Akt signalling pathway. Conversely, cells rely on this pathway to stimulate an antiviral response. The PI3K/Akt pathway is manipulated by a number of viruses, including DNA and RNA viruses and retroviruses. The aim of this review is to provide up-to-date information about the role of the PI3K-Akt pathway in infection with members of five different families of negative-sense ssRNA viruses. This pathway is hijacked for viral entry, regulation of endocytosis, suppression of premature apoptosis, viral protein expression, and replication. Although less common, the PI3K/Akt pathway can be downregulated as an immunomodulatory strategy or as a mechanism for inducing autophagy. Moreover, the cell activates this pathway as an antiviral strategy for interferon and cytokine production, among other strategies. Here, we present new data concerning the role of this pathway in infection with the paramyxovirus Newcastle disease virus (NDV). Our data seem to indicate that NDV uses the PI3K/Akt pathway to delay cell death and increase cell survival as a means of improving its replication. The interference of negative-sense ssRNA viruses with this essential pathway might have implications for the development of antiviral therapies.


Assuntos
Regulação da Expressão Gênica , Interações Hospedeiro-Patógeno/genética , Fosfatidilinositol 3-Quinase/genética , Proteínas Proto-Oncogênicas c-akt/genética , Infecções por Vírus de RNA/genética , Apoptose/genética , Autofagia/genética , Autofagia/imunologia , Citocinas/genética , Citocinas/imunologia , Endocitose/genética , Endocitose/imunologia , Filoviridae/genética , Filoviridae/metabolismo , Filoviridae/patogenicidade , Interações Hospedeiro-Patógeno/imunologia , Interferons/genética , Interferons/imunologia , Orthomyxoviridae/genética , Orthomyxoviridae/metabolismo , Orthomyxoviridae/patogenicidade , Paramyxoviridae/genética , Paramyxoviridae/metabolismo , Paramyxoviridae/patogenicidade , Fosfatidilinositol 3-Quinase/imunologia , Pneumovirinae/genética , Pneumovirinae/metabolismo , Pneumovirinae/patogenicidade , Biossíntese de Proteínas , Proteínas Proto-Oncogênicas c-akt/imunologia , Infecções por Vírus de RNA/imunologia , Infecções por Vírus de RNA/virologia , Rhabdoviridae/genética , Rhabdoviridae/metabolismo , Rhabdoviridae/patogenicidade , Transdução de Sinais , Proteínas Virais/genética , Proteínas Virais/imunologia , Internalização do Vírus , Replicação Viral
4.
Eur J Endocrinol ; 183(5): R133-R147, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32755992

RESUMO

The SARS-CoV-2 virus responsible for the COVID-19 pandemic has generated an explosion of interest both in the mechanisms of infection leading to dissemination and expression of this disease, and in potential risk factors that may have a mechanistic basis for disease propagation or control. Vitamin D has emerged as a factor that may be involved in these two areas. The focus of this article is to apply our current understanding of vitamin D as a facilitator of immunocompetence both with regard to innate and adaptive immunity and to consider how this may relate to COVID-19 disease. There are also intriguing potential links to vitamin D as a factor in the cytokine storm that portends some of the most serious consequences of SARS-CoV-2 infection, such as the acute respiratory distress syndrome. Moreover, cardiac and coagulopathic features of COVID-19 disease deserve attention as they may also be related to vitamin D. Finally, we review the current clinical data associating vitamin D with SARS-CoV-2 infection, a putative clinical link that at this time must still be considered hypothetical.


Assuntos
Imunidade Adaptativa/imunologia , Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina/imunologia , Imunidade Inata/imunologia , Imunocompetência/imunologia , Pulmão/imunologia , Pneumonia Viral/imunologia , Linfócitos T/imunologia , Vitamina D/imunologia , Peptídeos Catiônicos Antimicrobianos/imunologia , Autofagia/imunologia , Betacoronavirus , Defensinas/imunologia , Humanos , Pandemias , Linfócitos T Reguladores/imunologia , Células Th1/imunologia , Células Th17/imunologia , Células Th2/imunologia , Vitamina D/análogos & derivados
5.
Eur J Endocrinol ; 183(5): R133-R147, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: covidwho-695333

RESUMO

The SARS-CoV-2 virus responsible for the COVID-19 pandemic has generated an explosion of interest both in the mechanisms of infection leading to dissemination and expression of this disease, and in potential risk factors that may have a mechanistic basis for disease propagation or control. Vitamin D has emerged as a factor that may be involved in these two areas. The focus of this article is to apply our current understanding of vitamin D as a facilitator of immunocompetence both with regard to innate and adaptive immunity and to consider how this may relate to COVID-19 disease. There are also intriguing potential links to vitamin D as a factor in the cytokine storm that portends some of the most serious consequences of SARS-CoV-2 infection, such as the acute respiratory distress syndrome. Moreover, cardiac and coagulopathic features of COVID-19 disease deserve attention as they may also be related to vitamin D. Finally, we review the current clinical data associating vitamin D with SARS-CoV-2 infection, a putative clinical link that at this time must still be considered hypothetical.


Assuntos
Imunidade Adaptativa/imunologia , Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina/imunologia , Imunidade Inata/imunologia , Imunocompetência/imunologia , Pulmão/imunologia , Pneumonia Viral/imunologia , Linfócitos T/imunologia , Vitamina D/imunologia , Peptídeos Catiônicos Antimicrobianos/imunologia , Autofagia/imunologia , Betacoronavirus , Defensinas/imunologia , Humanos , Pandemias , Linfócitos T Reguladores/imunologia , Células Th1/imunologia , Células Th17/imunologia , Células Th2/imunologia , Vitamina D/análogos & derivados
6.
Cells ; 9(9)2020 08 24.
Artigo em Inglês | MEDLINE | ID: covidwho-727401

RESUMO

The preservation of cellular homeostasis requires the synthesis of new proteins (proteostasis) and organelles, and the effective removal of misfolded or impaired proteins and cellular debris. This cellular homeostasis involves two key proteostasis mechanisms, the ubiquitin proteasome system and the autophagy-lysosome pathway. These catabolic pathways have been known to be involved in respiratory exacerbations and the pathogenesis of various lung diseases, such as chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), idiopathic pulmonary fibrosis (IPF), acute lung injury (ALI), acute respiratory distress syndrome (ARDS), and coronavirus disease-2019 (COVID-19). Briefly, proteostasis and autophagy processes are known to decline over time with age, cigarette or biomass smoke exposure, and/or influenced by underlying genetic factors, resulting in the accumulation of misfolded proteins and cellular debris, elevating apoptosis and cellular senescence, and initiating the pathogenesis of acute or chronic lung disease. Moreover, autophagic dysfunction results in an impaired microbial clearance, post-bacterial and/or viral infection(s) which contribute to the initiation of acute and recurrent respiratory exacerbations as well as the progression of chronic obstructive and restrictive lung diseases. In addition, the autophagic dysfunction-mediated cystic fibrosis transmembrane conductance regulator (CFTR) immune response impairment further exacerbates the lung disease. Recent studies demonstrate the therapeutic potential of novel autophagy augmentation strategies, in alleviating the pathogenesis of chronic obstructive or restrictive lung diseases and exacerbations such as those commonly seen in COPD, CF, ALI/ARDS and COVID-19.


Assuntos
Autofagia/imunologia , Betacoronavirus , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/metabolismo , Progressão da Doença , Pneumonia Viral/imunologia , Pneumonia Viral/metabolismo , Lesão Pulmonar Aguda/imunologia , Lesão Pulmonar Aguda/metabolismo , Infecções por Coronavirus/virologia , Fibrose Cística/imunologia , Fibrose Cística/metabolismo , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Homeostase , Humanos , Fibrose Pulmonar Idiopática/imunologia , Fibrose Pulmonar Idiopática/metabolismo , Lisossomos/metabolismo , Pandemias , Pneumonia Viral/virologia , Doença Pulmonar Obstrutiva Crônica/imunologia , Doença Pulmonar Obstrutiva Crônica/metabolismo , Síndrome do Desconforto Respiratório do Adulto/imunologia , Síndrome do Desconforto Respiratório do Adulto/metabolismo
7.
Front Immunol ; 11: 1337, 2020.
Artigo em Inglês | MEDLINE | ID: covidwho-687353

RESUMO

Autophagy is a cellular recycling system found in almost all types of eukaryotic organisms. The system is made up of a variety of proteins which function to deliver intracellular cargo to lysosomes for formation of autophagosomes in which the contents are degraded. The maintenance of cellular homeostasis is key in the survival and function of a variety of human cell populations. The interconnection between metabolism and autophagy is extensive, therefore it has a role in a variety of different cell functions. The disruption or dysfunction of autophagy in these cell types have been implicated in the development of a variety of inflammatory diseases including asthma. The role of autophagy in non-immune and immune cells both lead to the pathogenesis of lung inflammation. Autophagy in pulmonary non-immune cells leads to tissue remodeling which can develop into chronic asthma cases with long term effects. The role autophagy in the lymphoid and myeloid lineages in the pathology of asthma differ in their functions. Impaired autophagy in lymphoid populations have been shown, in general, to decrease inflammation in both asthma and inflammatory disease models. Many lymphoid cells rely on autophagy for effector function and maintained inflammation. In stark contrast, autophagy deficient antigen presenting cells have been shown to have an activated inflammasome. This is largely characterized by a TH17 response that is accompanied with a much worse prognosis including granulocyte mediated inflammation and steroid resistance. The cell specificity associated with changes in autophagic flux complicates its targeting for amelioration of asthmatic symptoms. Differing asthmatic phenotypes between TH2 and TH17 mediated disease may require different autophagic modulations. Therefore, treatments call for a more cell specific and personalized approach when looking at chronic asthma cases. Viral-induced lung inflammation, such as that caused by SARS-CoV-2, also may involve autophagic modulation leading to inflammation mediated by lung resident cells. In this review, we will be discussing the role of autophagy in non-immune cells, myeloid cells, and lymphoid cells for their implications into lung inflammation and asthma. Finally, we will discuss autophagy's role viral pathogenesis, immunometabolism, and asthma with insights into autophagic modulators for amelioration of lung inflammation.


Assuntos
Asma/complicações , Asma/patologia , Autofagia/imunologia , Betacoronavirus , Infecções por Coronavirus/complicações , Infecções por Coronavirus/patologia , Pneumonia Viral/complicações , Pneumonia Viral/patologia , Animais , Asma/imunologia , Autofagossomos/metabolismo , Autofagia/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Células Dendríticas/metabolismo , Humanos , Linfócitos/metabolismo , Lisossomos/metabolismo , Células Mieloides/metabolismo , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/imunologia , Mucosa Respiratória/metabolismo , Transdução de Sinais/imunologia
8.
Front Immunol ; 11: 1337, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32733448

RESUMO

Autophagy is a cellular recycling system found in almost all types of eukaryotic organisms. The system is made up of a variety of proteins which function to deliver intracellular cargo to lysosomes for formation of autophagosomes in which the contents are degraded. The maintenance of cellular homeostasis is key in the survival and function of a variety of human cell populations. The interconnection between metabolism and autophagy is extensive, therefore it has a role in a variety of different cell functions. The disruption or dysfunction of autophagy in these cell types have been implicated in the development of a variety of inflammatory diseases including asthma. The role of autophagy in non-immune and immune cells both lead to the pathogenesis of lung inflammation. Autophagy in pulmonary non-immune cells leads to tissue remodeling which can develop into chronic asthma cases with long term effects. The role autophagy in the lymphoid and myeloid lineages in the pathology of asthma differ in their functions. Impaired autophagy in lymphoid populations have been shown, in general, to decrease inflammation in both asthma and inflammatory disease models. Many lymphoid cells rely on autophagy for effector function and maintained inflammation. In stark contrast, autophagy deficient antigen presenting cells have been shown to have an activated inflammasome. This is largely characterized by a TH17 response that is accompanied with a much worse prognosis including granulocyte mediated inflammation and steroid resistance. The cell specificity associated with changes in autophagic flux complicates its targeting for amelioration of asthmatic symptoms. Differing asthmatic phenotypes between TH2 and TH17 mediated disease may require different autophagic modulations. Therefore, treatments call for a more cell specific and personalized approach when looking at chronic asthma cases. Viral-induced lung inflammation, such as that caused by SARS-CoV-2, also may involve autophagic modulation leading to inflammation mediated by lung resident cells. In this review, we will be discussing the role of autophagy in non-immune cells, myeloid cells, and lymphoid cells for their implications into lung inflammation and asthma. Finally, we will discuss autophagy's role viral pathogenesis, immunometabolism, and asthma with insights into autophagic modulators for amelioration of lung inflammation.


Assuntos
Asma/complicações , Asma/patologia , Autofagia/imunologia , Betacoronavirus , Infecções por Coronavirus/complicações , Infecções por Coronavirus/patologia , Pneumonia Viral/complicações , Pneumonia Viral/patologia , Animais , Asma/imunologia , Autofagossomos/metabolismo , Autofagia/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Células Dendríticas/metabolismo , Humanos , Linfócitos/metabolismo , Lisossomos/metabolismo , Células Mieloides/metabolismo , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/imunologia , Mucosa Respiratória/metabolismo , Transdução de Sinais/imunologia
9.
Cells ; 9(8)2020 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-32722449

RESUMO

The outbreak of the coronavirus disease 2019 (COVID-19) pandemic has caused a global public health crisis. Viral infections may predispose pregnant women to a higher rate of pregnancy complications, including preterm births, miscarriage, and stillbirth. Despite reports of neonatal COVID-19, definitive proof of vertical transmission is still lacking. In this review, we summarize studies regarding the potential evidence for transplacental transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), characterize the expression of its receptors and proteases, describe the placental pathology and analyze virus-host interactions at the maternal-fetal interface. We focus on the syncytium, the barrier between mother and fetus, and describe in detail its physical and structural defense against viral infections. We further discuss the potential molecular mechanisms, whereby the placenta serves as a defense front against pathogens by regulating the interferon type III signaling, microRNA-triggered autophagy and the nuclear factor-κB pathway. Based on these data, we conclude that vertical transmission may occur but rare, ascribed to the potent physical barrier, the fine-regulated placental immune defense and modulation strategies. Particularly, immunomodulatory mechanisms employed by the placenta may mitigate violent immune response, maybe soften cytokine storm tightly associated with severely ill COVID-19 patients, possibly minimizing cell and tissue damages, and potentially reducing SARS-CoV-2 transmission.


Assuntos
Infecções por Coronavirus/transmissão , Transmissão Vertical de Doença Infecciosa , Placenta/imunologia , Placenta/virologia , Pneumonia Viral/transmissão , Complicações Infecciosas na Gravidez/imunologia , Autofagia/imunologia , Betacoronavirus , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Feminino , Humanos , Recém-Nascido , MicroRNAs/genética , MicroRNAs/metabolismo , Pandemias , Placenta/metabolismo , Placenta/patologia , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Gravidez , Complicações Infecciosas na Gravidez/virologia
10.
Adv Exp Med Biol ; 1207: 391-400, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32671761

RESUMO

Autophagy is an essential biological process for cells to maintain their homeostasis. It is a complex regulatory system that integrates innate and adaptive immunity. The role of autophagy in immune diseases has been paid more and more attention with the deepening of the mutual regulation and mechanism of autophagy and immunity. It is found that the aberrant autophagy is closely related to inflammatory diseases, including infections, adaptive immune-associated inflammation and inflammatory bowel disease. Autophagy plays critical roles in the activation of NLRP3 inflammasome, the clearance of bacterial and viral infections and what is more, the function of adaptive immune cells.


Assuntos
Autofagia/imunologia , Inflamação/imunologia , Inflamação/patologia , Imunidade Adaptativa , Humanos , Imunidade Inata , Infecções/imunologia , Infecções/microbiologia , Infecções/virologia , Inflamassomos , Doenças Inflamatórias Intestinais
11.
Adv Exp Med Biol ; 1207: 413-423, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32671764

RESUMO

Bacterial infection is a common clinical disease that can affect a variety of organs and tissues. Autophagy, as an important part of the innate immune response and adaptive immune response, plays an important role in the defense against bacterial infection. Bacteria can also evade autophagy by destroying or utilizing autophagy virulence proteins or related molecules. Studying the mechanism of autophagy in bacteria and its interaction with cells help to discover new pathogenic mechanisms of bacterial infection. This chapter introduces the possible mechanisms of autophagy during bacterial infections such as Salmonella and Mycobacterium tuberculosis, in order to discover new ways to prevent and control infectious diseases.


Assuntos
Autofagia , Infecções Bacterianas , Autofagia/imunologia , Infecções Bacterianas/imunologia , Infecções Bacterianas/microbiologia , Humanos , Mycobacterium tuberculosis/imunologia , Mycobacterium tuberculosis/patogenicidade , Salmonella/imunologia , Salmonella/patogenicidade , Virulência
12.
Adv Exp Med Biol ; 1207: 581-584, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32671776

RESUMO

Asthma is one of the most common diseases of the respiratory system, with typical pathogenesis and pathological changes. The current research shows that autophagy is mainly involved in the pathogenesis of asthma by regulating the body's innate and adaptive immune responses. At the same time, a large number of epidemiological studies have shown that multiple autophagy genes affect the risk of asthma at the level of genetic polymorphism. This chapter will explore the relationship between autophagy and asthma.


Assuntos
Asma , Autofagia , Asma/genética , Asma/imunologia , Autofagia/genética , Autofagia/imunologia , Humanos , Polimorfismo Genético
13.
Mediators Inflamm ; 2020: 7527953, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32724296

RESUMO

COVID-19 is a pandemic disease caused by the new coronavirus SARS-CoV-2 that mostly affects the respiratory system. The consequent inflammation is not able to clear viruses. The persistent excessive inflammatory response can build up a clinical picture that is very difficult to manage and potentially fatal. Modulating the immune response plays a key role in fighting the disease. One of the main defence systems is the activation of neutrophils that release neutrophil extracellular traps (NETs) under the stimulus of autophagy. Various molecules can induce NETosis and autophagy; some potent activators are damage-associated molecular patterns (DAMPs) and, in particular, the high-mobility group box 1 (HMGB1). This molecule is released by damaged lung cells and can induce a robust innate immunity response. The increase in HMGB1 and NETosis could lead to sustained inflammation due to SARS-CoV-2 infection. Therefore, blocking these molecules might be useful in COVID-19 treatment and should be further studied in the context of targeted therapy.


Assuntos
Alarminas/imunologia , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Armadilhas Extracelulares/imunologia , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/imunologia , Alarminas/antagonistas & inibidores , Autofagia/imunologia , Betacoronavirus/imunologia , Infecções por Coronavirus/patologia , Armadilhas Extracelulares/efeitos dos fármacos , Proteína HMGB1/antagonistas & inibidores , Proteína HMGB1/imunologia , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Interleucina-6/antagonistas & inibidores , Interleucina-6/imunologia , Pulmão/imunologia , Pulmão/patologia , Pandemias , Pneumonia Viral/patologia
14.
Mol Immunol ; 125: 162-171, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32688118

RESUMO

BACKGROUND: Baicalin has many biological properties such as anti-oxidation and anti-allergy. The current study aimed to explore the effect of Baicalin on allergic rhinitis (AR) and its potential mechanism of action. METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated by density gradient centrifugation. Expression levels of Th17 and Treg cells-related proteins in nasal mucosa and peripheral blood cells were detected by real-time quantitative PCR, flow cytometry and Western blot. The mice were randomly divided into Control, ovalbumin (OVA), l-Baicalin, H-Baicalin, DSGC, 3-MA, and H-Baicalin + Rapa groups. Changes of allergic rhinitis conditions and eosinophil infiltration of the mice were detected and scored by Diff-Quik staining, and histological changes were observed by Hematoxylin & Eosin (H&E) staining and Periodate Schiff (PAS) staining. Serological changes, expression levels of interleukin-17A (IL-17A), interleukin-10 (IL-10), eosinophilic cationic protein (ECP) and anti-OVA-specific antibodies were detected by Enzyme-linked immunosorbent assay (ELISA). RESULTS: Clinical case analysis found that AR patients had a Th17/Treg imbalance and activated autophagy, however, Baicalin restored Th17/Treg cell balance and inhibited autophagy in vitro. in vivo experiments demonstrated that Baicalin inhibited OVA-induced allergic nasal symptoms and the activation of autophagy pathway, which was the same as the regulation of 3-MA, while Rapa could weaken the effects of H-baicalin. Moreover, Baicalin reduced the infiltration of different inflammatory cells of the nasal lavage fluid, prevented the damages to epithelial cells, and improved nasal mucosal thickness and mucus secretion. In addition, Baicalin regulated the balance of mouse anti-OVA-specific antibody levels and expressions of Th17/Treg-associated cytokines. CONCLUSION: Our study revealed that Baicalin can be used to treat AR, and the effect is realized through inhibiting autophagy to regulate Th17/Treg cell differentiation.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Autofagia/efeitos dos fármacos , Flavonoides/farmacologia , Rinite Alérgica/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Animais , Autofagia/imunologia , Humanos , Camundongos , Linfócitos T Reguladores/imunologia , Células Th17/imunologia
15.
Cells ; 9(8)2020 07 25.
Artigo em Inglês | MEDLINE | ID: covidwho-698553

RESUMO

The outbreak of the coronavirus disease 2019 (COVID-19) pandemic has caused a global public health crisis. Viral infections may predispose pregnant women to a higher rate of pregnancy complications, including preterm births, miscarriage, and stillbirth. Despite reports of neonatal COVID-19, definitive proof of vertical transmission is still lacking. In this review, we summarize studies regarding the potential evidence for transplacental transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), characterize the expression of its receptors and proteases, describe the placental pathology and analyze virus-host interactions at the maternal-fetal interface. We focus on the syncytium, the barrier between mother and fetus, and describe in detail its physical and structural defense against viral infections. We further discuss the potential molecular mechanisms, whereby the placenta serves as a defense front against pathogens by regulating the interferon type III signaling, microRNA-triggered autophagy and the nuclear factor-κB pathway. Based on these data, we conclude that vertical transmission may occur but rare, ascribed to the potent physical barrier, the fine-regulated placental immune defense and modulation strategies. Particularly, immunomodulatory mechanisms employed by the placenta may mitigate violent immune response, maybe soften cytokine storm tightly associated with severely ill COVID-19 patients, possibly minimizing cell and tissue damages, and potentially reducing SARS-CoV-2 transmission.


Assuntos
Infecções por Coronavirus/transmissão , Transmissão Vertical de Doença Infecciosa , Placenta/imunologia , Placenta/virologia , Pneumonia Viral/transmissão , Complicações Infecciosas na Gravidez/imunologia , Autofagia/imunologia , Betacoronavirus , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Feminino , Humanos , Recém-Nascido , MicroRNAs/genética , MicroRNAs/metabolismo , Pandemias , Placenta/metabolismo , Placenta/patologia , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Gravidez , Complicações Infecciosas na Gravidez/virologia
16.
Mol Immunol ; 124: 18-24, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32485435

RESUMO

Autophagy has been identified as an important immune regulatory mechanism. Recent studies have linked macrophage autophagy with innate immune responses against Mycobacterium tuberculosis (M. tuberculosis), which can survive within macrophages by blocking fusion of the phagosome with lysosomes. These findings suggest that autophagy is a regulatable cellular mechanism of M. tuberculosis defense in macrophages. Transcriptomic profiles in human blood in TB patients suggest that M. tuberculosis affects autophagy related pathways. In order to better understand the role of macrophage autophagy in enhancing protective immunity against M. tuberculosis, in this study, we investigate the effects of the autophagy activators rapamycin and LPS in macrophage autophagy and immunity against M. tuberculosis. We confirm that rapamycin and LPS induce autophagy in M. tuberculosis infected THP-1-derived macrophages or PMA primed THP-1 macrophages [THP-1(A)]. LPS restores M. tuberculosis-inhibited IL-12 synthesis and secretion in THP-1(A) cells via autophagy. Similarly, autophagy activators increase IL-12 synthesis and secretion in THP-1(A) cells. These studies demonstrate the importance of autophagy in M. tuberculosis elimination in macrophages and may lead to novel therapies for tuberculosis and other bacterial infections.


Assuntos
Autofagia/imunologia , Macrófagos/imunologia , Mycobacterium tuberculosis/imunologia , Tuberculose/imunologia , Autofagia/efeitos dos fármacos , Humanos , Lipopolissacarídeos/imunologia , Lipopolissacarídeos/farmacologia
17.
Proc Natl Acad Sci U S A ; 117(25): 14376-14385, 2020 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-32513718

RESUMO

Temporally harmonized elimination of damaged or unnecessary organelles and cells is a prerequisite of health. Under Type 2 inflammatory conditions, human airway epithelial cells (HAECs) generate proferroptotic hydroperoxy-arachidonoyl-phosphatidylethanolamines (HpETE-PEs) as proximate death signals. Production of 15-HpETE-PE depends on activation of 15-lipoxygenase-1 (15LO1) in complex with PE-binding protein-1 (PEBP1). We hypothesized that cellular membrane damage induced by these proferroptotic phospholipids triggers compensatory prosurvival pathways, and in particular autophagic pathways, to prevent cell elimination through programmed death. We discovered that PEBP1 is pivotal to driving dynamic interactions with both proferroptotic 15LO1 and the autophagic protein microtubule-associated light chain-3 (LC3). Further, the 15LO1-PEBP1-generated ferroptotic phospholipid, 15-HpETE-PE, promoted LC3-I lipidation to stimulate autophagy. This concurrent activation of autophagy protects cells from ferroptotic death and release of mitochondrial DNA. Similar findings are observed in Type 2 Hi asthma, where high levels of both 15LO1-PEBP1 and LC3-II are seen in HAECs, in association with low bronchoalveolar lavage fluid mitochondrial DNA and more severe disease. The concomitant activation of ferroptosis and autophagy by 15LO1-PEBP1 complexes and their hydroperoxy-phospholipids reveals a pathobiologic pathway relevant to asthma and amenable to therapeutic targeting.


Assuntos
Araquidonato 15-Lipoxigenase/metabolismo , Asma/imunologia , Autofagia/imunologia , Células Epiteliais/patologia , Ferroptose/imunologia , Proteína de Ligação a Fosfatidiletanolamina/metabolismo , Adulto , Animais , Asma/diagnóstico , Asma/patologia , Líquido da Lavagem Broncoalveolar/citologia , Linhagem Celular , Sobrevivência Celular/imunologia , Células Epiteliais/imunologia , Feminino , Técnicas de Inativação de Genes , Humanos , Ácidos Hidroxieicosatetraenoicos/imunologia , Ácidos Hidroxieicosatetraenoicos/metabolismo , Interleucina-13/imunologia , Interleucina-13/metabolismo , Masculino , Camundongos , Proteínas Associadas aos Microtúbulos/metabolismo , Simulação de Dinâmica Molecular , Proteína de Ligação a Fosfatidiletanolamina/genética , Fosfatidiletanolaminas/imunologia , Fosfatidiletanolaminas/metabolismo , Cultura Primária de Células , Ligação Proteica/imunologia , Índice de Gravidade de Doença
18.
Nature ; 581(7806): 100-105, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32376951

RESUMO

Immune evasion is a major obstacle for cancer treatment. Common mechanisms of evasion include impaired antigen presentation caused by mutations or loss of heterozygosity of the major histocompatibility complex class I (MHC-I), which has been implicated in resistance to immune checkpoint blockade (ICB) therapy1-3. However, in pancreatic ductal adenocarcinoma (PDAC), which is resistant to most therapies including ICB4, mutations that cause loss of MHC-I are rarely found5 despite the frequent downregulation of MHC-I expression6-8. Here we show that, in PDAC, MHC-I molecules are selectively targeted for lysosomal degradation by an autophagy-dependent mechanism that involves the autophagy cargo receptor NBR1. PDAC cells display reduced expression of MHC-I at the cell surface and instead demonstrate predominant localization within autophagosomes and lysosomes. Notably, inhibition of autophagy restores surface levels of MHC-I and leads to improved antigen presentation, enhanced anti-tumour T cell responses and reduced tumour growth in syngeneic host mice. Accordingly, the anti-tumour effects of autophagy inhibition are reversed by depleting CD8+ T cells or reducing surface expression of MHC-I. Inhibition of autophagy, either genetically or pharmacologically with chloroquine, synergizes with dual ICB therapy (anti-PD1 and anti-CTLA4 antibodies), and leads to an enhanced anti-tumour immune response. Our findings demonstrate a role for enhanced autophagy or lysosome function in immune evasion by selective targeting of MHC-I molecules for degradation, and provide a rationale for the combination of autophagy inhibition and dual ICB therapy as a therapeutic strategy against PDAC.


Assuntos
Adenocarcinoma/imunologia , Autofagia/imunologia , Carcinoma Ductal Pancreático/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Neoplasias Pancreáticas/imunologia , Evasão Tumoral/imunologia , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/patologia , Animais , Apresentação do Antígeno/efeitos dos fármacos , Apresentação do Antígeno/imunologia , Autofagia/efeitos dos fármacos , Autofagia/genética , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/imunologia , Linhagem Celular Tumoral , Cloroquina/farmacologia , Feminino , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Masculino , Camundongos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Evasão Tumoral/efeitos dos fármacos
19.
Neuron ; 106(5): 789-805.e5, 2020 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-32220666

RESUMO

DNA sequence variants in the TBK1 gene associate with or cause sporadic or familial amyotrophic lateral sclerosis (ALS). Here we show that mice bearing human ALS-associated TBK1 missense loss-of-function mutations, or mice in which the Tbk1 gene is selectively deleted in motor neurons, do not display a neurodegenerative disease phenotype. However, loss of TBK1 function in motor neurons of the SOD1G93A mouse model of ALS impairs autophagy, increases SOD1 aggregation, and accelerates early disease onset without affecting lifespan. By contrast, point mutations that decrease TBK1 kinase activity in all cells also accelerate disease onset but extend the lifespan of SOD1 mice. This difference correlates with the failure to activate high levels of expression of interferon-inducible genes in glia. We conclude that loss of TBK1 kinase activity impacts ALS disease progression through distinct pathways in different spinal cord cell types and further implicate the importance of glia in neurodegeneration.


Assuntos
Esclerose Amiotrófica Lateral/genética , Autofagia/genética , Microglia/imunologia , Neurônios Motores/metabolismo , Proteínas Serina-Treonina Quinases/genética , Superóxido Dismutase-1/genética , Idade de Início , Esclerose Amiotrófica Lateral/imunologia , Animais , Autofagia/imunologia , Modelos Animais de Doenças , Progressão da Doença , Técnicas de Introdução de Genes , Inflamação , Mutação com Perda de Função , Camundongos , Camundongos Knockout , Mutação de Sentido Incorreto , Junção Neuromuscular/genética , Proteínas Serina-Treonina Quinases/imunologia , Taxa de Sobrevida
20.
Biochim Biophys Acta Rev Cancer ; 1873(2): 188357, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32147543

RESUMO

Caspase-8 is a cysteine - aspartate specific protease that classically triggers the extrinsic apoptotic pathway, in response to the activation of cell surface Death Receptors (DRs) like FAS, TRAIL-R and TNF-R. Besides it's roles in triggering death receptor-mediated apoptosis, Caspase-8 has also been implicated in the onsets of anoikis, autophagy and pyroptosis. Furthermore, Caspase-8 also plays a crucial pro-survival function by inhibiting an alternative form of programmed cell death called necroptosis. Low expression levels of pro-Caspase-8 is therefore associated with the malignant transformation of cancers. However, the long-held notion that pro-Caspase-8 expression/activity is generally lost in most cancers, thereby contributing to apoptotic escape and enhanced resistance to anti-cancer therapeutics, has been found to be true for only a minority of cancers types. In the majority of cases, pro-Caspase-8 expression is maintained and sometimes elevated, while it's apoptotic activity is regulated through different mechanisms. This supports the notion that the non-apoptotic functions of Caspase-8 offer growth advantage in these cancer types and have, therefore, gained renewed interest in the recent years. In light of these reasons, a number of therapeutic approaches have been employed, with the intent of targeting pro-Caspase-8 in cancer cells. In this review, we would attempt to discuss - the classic roles of Caspase-8 in initiating apoptosis; it's non-apoptotic functions; it's the clinical significance in different cancer types; and the therapeutic applications exploiting the ability of pro-Caspase-8 to regulate various cellular functions.


Assuntos
Caspase 8/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias/patologia , Animais , Apoptose/genética , Apoptose/imunologia , Autofagia/genética , Autofagia/imunologia , Caspase 8/genética , Ciclo Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Sobrevivência Celular/genética , Citocinas/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , Regulação para Baixo , Humanos , Inflamassomos/imunologia , Inflamassomos/metabolismo , Camundongos , Necroptose/genética , Necroptose/imunologia , Neoplasias/genética , Neoplasias/imunologia , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Regulação para Cima
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